ZA200406356B - Embryonic-like stem cells derived from post-partummammalian placenta and uses and methods of treatm ent using said cells - Google Patents
Embryonic-like stem cells derived from post-partummammalian placenta and uses and methods of treatm ent using said cells Download PDFInfo
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- ZA200406356B ZA200406356B ZA200406356A ZA200406356A ZA200406356B ZA 200406356 B ZA200406356 B ZA 200406356B ZA 200406356 A ZA200406356 A ZA 200406356A ZA 200406356 A ZA200406356 A ZA 200406356A ZA 200406356 B ZA200406356 B ZA 200406356B
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0603—Embryonic cells ; Embryoid bodies
- C12N5/0605—Cells from extra-embryonic tissues, e.g. placenta, amnion, yolk sac, Wharton's jelly
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0607—Non-embryonic pluripotent stem cells, e.g. MASC
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0413—Blood
- A61M2202/0462—Placental blood, umbilical cord blood
Description
EMBRYONIC-LIKE STEM CELLS DERIVED FROM
POST-PARTUM MAMMALIAN PLACENTA, AND USES
AND METHODS OF TREATMENT USING SAID CELLS
1. INTRODUCTION
The present invention relates to the use of embryonic-like stem cells that originate from a post-partum placenta with conventional cord blood compositions or other stem or progenitor cells. The embryonic-like stem cells can be used alone or in a mixture with other stem cell populations. In accordance with the present invention, the embryonic-like stem cells may be mixed with other stem cell populations, including but not limited to, umbilical cord blood, fetal and neonatal hematopoietic stem cells and progenitor cells, human stem cells and progenitor cells derived from bone marrow. The embryonic-like stem cells and the mixed populations of embryonic-like stem cells and stem cells have a multitude of uses and applications, including but not limited to, therapeutic uses for transplantation, diagnostic and research uses. The embryonic-like stem cells and the mixed populations are also useful in the treatment of diseases or disorders, including vascular disease, neurological diseases or disorders, autoimmune diseases or disorders, diseases or disorders involving inflammation, and cancer or the disorders associated therewith. In particular, the embryonic-like stem cells or mixtures including them are administered in high doses and without HLA typing. 2. BACKGROUND OF THE INVENTION
There is considerable interest in the identification, isolation and generation of human stem cells. Human stem cells are totipotential or pluripotential precursor cells capable of generating a variety of mature human cell lineages. This ability serves as the basis for the cellular differentiation and specialization necessary for organ and tissue development.
Recent success at transplanting such stem cells have provided new clinical tools to reconstitute and/or supplement bone marrow after myeloablation due to disease, exposure to toxic chemical and/or radiation. Further evidence exists that demonstrates that stem cells can be employed to repopulate many, if not all, tissues and restore physiologic and anatomic functionality. The application of stem cells in tissue engineering, gene therapy delivery and cell therapeutics is also advancing rapidly.
Many different types of mammalian stem cells have been characterized. For example, embryonic stem cells, embryonic germ cells, adult stem cells or other committed stem cells or progenitor cells are known. Certain stem cells have not only been isolated and characterized but have also been cultured under conditions to allow differentiation to a limited extent. A basic problem remains, however, in that obtaining sufficient quantities . and populations of human stem cells which are capable of differentiating into all cell types : is near impossible. Stem cells are in critically short supply. These are important for the ‘ 5 treatment of a wide variety of disorders, including malignancies, inborn errors of metabolism, hemoglobinopathies, and immunodeficiencies. It would be highly advantageous to have a source of more embryonic stem cells.
Obtaining sufficient numbers of human stem cells has been problematic for several reasons. First, isolation of normally occurring populations of stem cells in adult tissues has been technically difficult and costly due, in part, to very limited quantity found in blood or tissue. Secondly, procurement of these cells from embryos or fetal tissue, including abortuses, has raised religious and ethical concerns. The widely held belief that the human embryo and fetus constitute independent life has prompted governmental restrictions on the use of such sources for all purposes, including medical research. Alternative sources that do not require the use of cells procured from embryonic or fetal tissue are therefore essential for further progress in the use of stem cells clinically. There are, however, few viable alternative sources of stem cells, particularly human stem cells, and thus supply is limited.
Furthermore, harvesting of stem cells from alternative sources in adequate amounts for therapeutic and research purposes is generally laborious, involving, e.g., harvesting of cells or tissues from a donor subject or patient, culturing and/or propagation of cells in vitro, dissection, etc.
For example, Caplan et al. (U.S. Patent No. 5,486,359 entitled “Human mesenchymal stem cells,” issued January 23, 1996), discloses human mesenchymal stem cell (h(MSC) compositions derived from the bone marrow that serve as the progenitors for mesenchymal cell lineages. Caplan ef al. discloses that hMSCs are identified by specific cell surface markers that are identified with monoclonal antibodies. Homogeneous hMSC compositions are obtained by positive selection of adherent marrow or periosteal cells that are free of markers associated with either hematopoietic cell or differentiated mesenchymal cells. These isolated mesenchymal cell populations display epitopic characteristics associated with mesenchymal stem cells, have the ability to regenerate in culture without differentiating, and have the ability to differentiate into specific mesenchymal lineages i when either induced in vitro or placed in vivo at the site of damaged tissue. The drawback of such methods, however, is that they require harvesting of marrow or periosteal cells from a donor, from which the MSCs must be subsequently isolated.
Hu et al. (WO 00/73421 entitled “Methods of isolation, cryopreservation, and therapeutic use of human amniotic epithelial cells,” published December 7, 2000) discloses } human amniotic epithelial cells derived from placenta at delivery that are isolated, cultured, cryopreserved for future use, or induced to differentiate. According to Hu ef a/. a placenta . 5 is harvested immediately after delivery and the amniotic membrane separated from the chorion, e.g., by dissection. Amniotic epithelial cells are isolated from the amniotic membrane according to standard cell isolation techniques. The disclosed cells can be cultured in various media, expanded in culture, cryopreserved, or induced to differentiate.
Hu er al. discloses that amniotic epithelial cells are multipotential (and possibly pluripotential), and can differentiate into epithelial tissues such as corneal surface epithelium or vaginal epithelium. The drawback of such methods, however, is that they are labor-intensive and the yield of stem cells is very low. For example, to obtain sufficient numbers of stem cells for typical therapeutic or research purposes, amniotic epithelial cells must be first isolated from the amnion by dissection and cell separation techniques, then cultured and expanded in vitro.
Umbilical cord blood ("cord blood") is a known alternative source of hematopoietic progenitor stem cells. Stem cells from cord blood are routinely cryopreserved for use in hematopoietic reconstitution, a widely used therapeutic procedure used in bone marrow and other related transplantations (see e.g., Boyse et al., U.S. 5,004,681, “Preservation of Fetal and Neonatal Hematopoietin Stem and Progenitor Cells of the Blood”, Boyse et al., U.S.
Patent No. 5,192,553, entitled “Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use”, issued March 9, 1993). Conventional techniques for the collection of cord blood are based on the use of a needle or cannula, which is used with the aid of gravity to drain cord blood from (i.e., exsanguinate) the placenta (Boyse et al., U.S. Patent No. 5,192,553, issued
March 9, 1993; Boyse et al., U.S. Patent No. 5,004, 681, issued April 2, 1991; Anderson,
U.S. Patent No. 5,372,581, entitled Method and apparatus for placental blood collection, issued December 13, 1994; Hessel ef al., U.S. Patent No. 5,415,665, entitled Umbilical cord clamping, cutting, and blood collecting device and method, issued May 16, 1995). The needle or cannula is usually placed in the umbilical vein and the placenta is gently massaged ’ to aid in draining cord blood from the placenta. Thereafter, however, the drained placenta has been regarded as having no further use and has typically been discarded. A major limitation of stem cell procurement from cord blood, moreover, has been the frequently inadequate volume of cord blood obtained, resulting in insufficient cell numbers to effectively reconstitute bone marrow after transplantation.
Naughton ef al. (U.S. Patent No. 5,962,325 entitled “Three-dimensional stromal tissue cultures” issued October 5, 1999) discloses that fetal cells, including fibroblast-like : cells and chondrocyte-progenitors, may be obtained from umbilical cord or placenta tissue or umbilical cord blood. ’ 5 Kraus et al. (U.S. Patent No. 6,338,942, entitled “Selective expansion of target cell populations”, issued January 15, 2002) discloses that a predetermined target population of cells may be selectively expanded by introducing a starting sample of cells from cord blood or peripheral blood into a growth medium, causing cells of the target cell population to divide, and contacting the cells in the growth medium with a selection element comprising binding molecules with specific affinity (such as a monoclonal antibody for CD34) for a predetermined population of cells (such as CD34 cells), so as to select cells of the predetermined target population from other cells in the growth medium.
Rodgers et al. (U.S. Patent No. 6,335,195 entitled “Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation,” issued January 1, 2002) discloses methods for ex vivo culture of hematopoietic and mesenchymal stem cells and the induction of lineage-specific cell proliferation and differentiation by growth in the presence of angiotensinogen, angiotensin I (AI), Al analogues, Al fragments and analogues thereof, angiotensin II (AI), AIl analogues, All fragments or analogues thereof or All AT, type 2 receptor agonists, either alone or in combination with other growth factors and cytokines. The stem cells are derived from bone marrow, peripheral blood or umbilical cord blood. The drawback of such methods, however, is that such ex vivo methods for inducing proliferation and differentiation of stem cells are time-consuming, as discussed above, and also result in low yields of stem cells.
Because of restrictions on the collection and use of stem cells, and the inadequate numbers of cells typically collected from cord blood, stem cells are in critically short supply. Stem cells have the potential to be used in the treatment of a wide variety of disorders, including malignancies, inbom errors of metabolism, hemoglobinopathies, and immunodeficiencies. There is a critical need for a readily accessible source of large numbers of human stem cells for a variety of therapeutic and other medically related ) 30 purposes. The present invention addresses that need and others.
Additionally, there remains a need for the treatment of neurological conditions such i as amylotrophic lateral sclerosis (ALS). Although recent studies using irradiated mouse models of familial ALS, a less-common form of ALS, have suggested that cord blood may be useful in the treatment of this disease, the source issue discussed above makes this option less than ideal. See Ende et al., Life Sci. 67:53059 (2000). Thus, there remains a need for stem or progenitor cell populations that can be used to treat diseases, particularly larger amounts of these populations when diseases such as ALS are being treated. 3. SUMMARY OF THE INVENTION : 5 The present invention relates to cord blood compositions or stem or progenitor cells therefrom in which said compositions are supplemented with or contacted with embryonic- like stem cells that originate from a post-partum placenta. The embryonic-like stem cells which are the subject of other applications can be used herein as a composition or a mixture with other stem or progenitor cell populations. In accordance with the present invention, the embryonic-like stem cells may contacted with other stem or progenitor cell populations, including but not limited to, umbilical cord blood, fetal and neonatal hematopoietic stem cells and progenitor cells, human stem cells and progenitor cells derived from bone marrow.
The embryonic-like stem cells and the mixed populations of embryonic-like stem cells and stem or progenitor cells have a multitude of uses and applications, including but not limited to, therapeutic uses for transplantation and treatment and prevention of disease, and diagnostic and research uses.
In accordance with the present invention, populations of stem cells are mixed with populations of embryonic-like stem cells in order to supplement, augment or enhance the : concentrations of pluripotent and multipotent stem cells in the stem cell populations. for example, in one embodiment, umbilical cord blood, or stem or progenitor cells therefrom, is augmented or contacted with the embryonic-like stem cells of the invention prior to administration to the patient. It is recognized that the embryonic-like stem cells may also be administered simultaneously or sequentially with the umbilical cord blood, or cells therefrom, However, contacting the cells of each before administration is preferred.
The embryonic-like stem cells of the invention may be characterized by the presence of the following cell surface markers: CD10, CD29, CD44, CD54, CD90, SH2, SH3, SH4,
OCT-4 and ABC-p, and the absence of the following cell surface markers: CD34, CD38,
CD45, SSEA3 and SSEA4. In a preferred embodiment, such embryonic-like stem cells may be characterized by the presence of cell surface markers OCT-4 and APC-p. Embryonic- like stem cells originating from placenta have characteristics of embryonic stem cells but ) are not derived from the embryo. In other words, the invention encompasses mixtures of cord blood and embryonic-like stem cells isolated from a placenta that are OCT-4+ and/or
ABC-p+. Such embryonic-like stem cells are as versatile (e.g., pluripotent) as human embryonic stem cells.
In accordance with the present invention, populations of stem cells are mixed with embryonic-like stem cells that are pluripotent or multipotent. Such embryonic-like stem } cells can be isolated from the perfused placenta at different time points e.g., CD34+ /CD38+, CD34+/CD38-, and CD34-/CD38- hematopoietic cells. In one embodiment, such . 5 cells may be used to supplement populations of hematopoietic stem cells, such as those found in umbilical cord blood, according to the methods of the vention. : The invention also provides a composition in which a mixture of stem cells with embryonic-like stem cells is contained within one bag or container. In a preferred embodiment, the composition is a pharmaceutically acceptable unit dose composition. In another embodiment, the invention provides a composition in which a population of stem cells and a population of embryonic-like stem cells are contained within two separate bags or containers. In certain embodiments, such a "two bag" kit may be mixed prior, in particular immediately prior to, or at the time of administration to a patient in need thereof.
In other embodiments, the contents of each bag may be administered separately to a patient, wherein the mixing of the two cell populations occurs in vivo. In other embodiments, the container is sealed, air tight, and sterile.
The present invention relates to populations of stem cells are mixed with embryonic- like stem cells. In accordance with the present invention, stems cells that may be mixed with embryonic-like stem cells include, but are not limited to, umbilical cord blood, fetal and neonatal hematopoietic stem cells and progenitor cells, human stem cells and progenitor cells derived from bone marrow. In a preferred embodiment of the present invention, the embryonic-like stem cells of the invention are mixed with umbilical cord blood.
The present invention also provides methods of treating a patient in need thereof by administration of a population of stem cells supplemented with embryonic-like stem cells.
In one embodiment, the supplementation of the population of cord blood cells with embryonic-like stem cells occurs by mixing the stem cells and embryonic-like stem cells prior to administration of the combined or “spiked” population to the patient. In another embodiment, the supplementation of the population of stem cells with embryonic-like stem cells occurs upon administration of the supplemented population to the patient, e.g., by simultaneous administration of the cord blood cells and the embryonic-like stem cells. In ’ another embodiment, the supplementation of the population of stem cells with embryonic- like stem cells occurs after administration of the cord blood cells to the patient, e.g., by ) administering the embryonic-stem cells separately from, and before or after, administration of the stem cells.
According to the invention, populations of stem cells, e.g., umbilical cord blood, supplemented with embryonic-like stem cells from the placenta have a multitude of uses, including prophylactic, therapeutic and diagnostic uses. The supplemented populations of stem cells can be used for transplantation and/or to treat or prevent disease. In one . 5 embodiment of the invention, the supplemented populations of cells are used to renovate and repopulate tissues and organs, thereby replacing or repairing diseased tissues, organs or portions thereof. In another embodiment, the supplemented populations of stem cells can be used as a diagnostic to screen for genetic disorders or a predisposition for a particular disease or disorder.
In another embodiment, the invention provides a method for isolating other embryonic-like and/or multipotent or pluripotent stem cells from an extract or perfusate of a exsanguinated placenta and using them to supplement populations of cord blood cells according to the methods of the invention.
The present invention also provides pharmaceutical compositions that comprise populations of stem cells, e.g., umbilical cord blood cells, that have been supplemented with one or more populations of embryonic-like stem cells of the invention.
The present invention provides an isolated homogenous population of human placental stem cells that has the potential to differentiate into all cell types. In another embodiment, the population of human placental stem cells has the potential to differentiate into one cell type. In yet another embodiment, the population of human placental stem cells has the potential to differentiate into several different cell types. Such cells may be used to supplement populations of stem cells, e.g., umbilical cord blood, according to the methods of the invention.
The invention also encompasses pharmaceutical compositions that comprise populations of hematopoietic stem cells supplemented with one or more populations of cells that have high concentrations (or larger populations) of homogenous hematopoietic stem cells including, but not limited to, CD34+ /CD38- cells; CD34-/CD38- cells, and CD133* cells. One or more of these cell populations can be used with, or mixed with, hematopoietic stem cells i.e., CD34+/CD38+ hematopoietic cells, obtained from umbilical cord blood or other sources, for transplantation and other uses. ’ The present invention also provides methods of mixing a population of stem, progenitor or cord blood cells, including banked or cryopreserved cord blood cells, with a ) population of embryonic-like stem cells. In one embodiment, the two populations are physically mixed. In another aspect of this embodiment, the two populations are physically mixed and then treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation. In another aspect of this embodiment, the stem cells and/or the embryonic-like stem cells are treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation and then physically mixed. In one embodiment, the mixed populations are treated with a growth factor to induce differentiation into a variety of cell types. In another embodiment, the mixed populations are treated with a growth factor to induce differentiation into a particular cell type. In another embodiment, the mixed populations are treated with a growth factor to prevent or suppress differentiation into a particular cell type. In certain embodiments, the culture conditions can be controlled, e.g., the mixed population of cells can be treated with a specific cocktail of cytokines or interleukins to direct or induce differentiation to a specific cell type.
In another embodiment, the invention provides a method of treating a patient in need thereof comprising administration of a plurality of umbilical cord blood cells and a plurality of embryonic-like stem cells.
In another embodiment, the invention provides a method of treating myelodysplasia which comprises administering umbilical cord blood cells (or stem cells isolated therefrom) and embryonic-like stem cells to a patient in need thereof.
The invention also relates to new uses of human placental stem cells (embryonic-like stem cells). Methods of treating or preventing disease with the compositions containing embryonic-like stem cells and other stem or progenitor cells or sources thereof are also encompassed herein. Similarly, methods of dosing such compositions are encompassed. finally, it should be noted that the compositions of the invention can contain stem or progenitor cell populations from multiple donors. The invention includes the use of non-
HLA matched compositions in patients as well as HLA-matched compositions. blood type matching with the patient is preferred but not required when the compositions containing both embryonic-like stem cells and stem or progenitor cells are used. 3.1. DEFINITIONS
As used herein, the term “bioreactor” refers to an ex vivo system for propagating cells, producing or expressing biological materials and growing or culturing cells tissues, organoids, viruses, proteins, polynucleotides and microorganisms.
As used herein, the terms “cord blood” and “umbilical cord blood” are : interchangeable.
As used herein, the term “embryonic stem cell” refers to a cell that is derived from ) the inner cell mass of a blastocyst (e.g., a 4- to 5-day-old human embryo) and that is pluripotent.
As used herein, the term “embryonic-like stem cell” refers to a cell that is not derived from the inner cell mass of a blastocyst. As used herein, an “embryonic-like stem cell” may also be referred to as a “placental stem cell,” preferably a human placental stem cell derived from a post-partum perfused placenta. An embryonic-like stem cell is preferably pluripotent. However, the stem cells which may be obtained from the placenta include embryonic-like stem cells, multipotent cells, and committed progenitor cells. } 5 According to the methods of the invention, embryonic-like stem cells derived from the placenta may be collected from the isolated placenta once it has been exsanguinated and perfused for a period of time sufficient to remove residual cells.
As used herein, the term “exsanguinated” or “exsanguination,” when used with respect to the placenta, refers to the removal and/or draining of substantially all cord blood from the placenta. In accordance with the present invention, exsanguination of the placenta can be achieved by, for example, but not by way of limitation, draining, gravity induced efflux, massaging, squeezing, pumping, etc. In a preferred embodiment, exsanguination of the placenta may further be achieved by perfusing, rinsing or flushing the placenta with a fluid that may or may not contain agents, such as anticoagulants, to aid in the exsanguination of the placenta.
As used herein, the term to "mix" means to combine or blend into one mass or mixture; to put together into one mass so that the constituent parts are more or less homogeneous; to create or form by combining ingredients; to form by admixture, augmentation, supplementation, or commingling; or to add an ingredient or element to another ingredient or element, and vice-versa.
As used herein, the term “perfuse” or “perfusion” refers to the act of pouring or passaging a fluid over or through an organ or tissue, preferably the passage of fluid through an organ or tissue with sufficient force or pressure to remove any residual cells, e.g., non- attached cells from the organ or tissue. As used herein, the term “perfusate” refers to the fluid collected following its passage through an organ or tissue. In a preferred embodiment, the perfusate contains one or more anticoagulants.
As used herein, the term “exogenous cell” refers to a “foreign” cell, i.e., a heterologous cell (i.e., a “non-self” cell derived from a source other than the placental donor) or autologous cell (i.e., a “self” cell derived from the placental donor) that is-derived from an organ or tissue other than the placenta. ; As used herein, the term “organoid” refers to an aggregation of one or more cell types assembled in superficial appearance or in actual structure as any organ or gland of a ) mammalian body, preferably the human body.
As used herein, the term “multipotent cell” refers to a cell that has the capacity to grow into any of subset of the mammalian body’s approximately 260 cell types. Unlike a pluripotent cell, a multipotent cell does not have the capacity to form all of the cell types.
As used herein, the term “pluripotent cell” refers to a cell that has complete differentiation versatility, i.e., the capacity to grow into any of the mammalian body’s } approximately 260 cell types. A pluripotent cell can be self-renewing, and can remain dormant or quiescent within a tissue. Unlike a totipotent cell (e.g., a fertilized, diploid egg cell), an embryonic stem cell cannot usually form a new blastocyst.
As used herein, the term “progenitor cell” refers to a cell that is committed to differentiate into a specific type of cell or to form a specific type of tissue.
As used herein, the term “stem cell” refers to a master cell that can reproduce indefinitely to form the specialized cells of tissues and organs. A stem cell is a developmentally pluripotent or multipotent cell. A stem cell can divide to produce two daughter stem cells, or one daughter stem cell and one progenitor (“transit”) cell, which then proliferates into the tissue’s mature, fully formed cells. The “stem cell” used herein includes “progenitor cells” unless otherwise noted.
As used herein, the term “totipotent cell” refers to a cell that is able to form a complete embryo (e.g., a blastocyst). 4. DETAILED DESCRIPTION OF THE INVENTION
The present invention is based in part on the unexpected discovery that embryonic- like stem cells produced by the exsanguinated, perfused and/or cultured placenta are pluripotent stem cells that can be readily differentiated into any desired cell type. These embryonic-like stem cells can be used to supplement, augment or enhance populations of stem cells, including, but not limited to umbilical cord blood, fetal and neonatal hematopoietic stem cells and progenitor cells, human stem cells and progenitor cells derived from bone marrow. In accordance with the present invention, populations of stem cells are mixed with populations of embryonic-like stem cells in order to supplement, augment or enhance the concentrations of pluripotent and multipotent stem cells in the stem cell populations. In accordance with the present invention, the populations of stem cells mixed with populations of embryonic-like stem cells have a multitude of uses and applications, including but not limited to, therapeutic uses for transplantation and treatment and prevention of disease, and diagnostic and research uses. ) The invention also provides a composition in which a mixture of stem cells and embryonic-like stem cells is contained within one bag or container. In another embodiment, the invention provides a composition in which a population of stem cells and a population of embryonic-like stem cells are contained within two separate bags or containers. In certain embodiments, such a "two bag" composition may be mixed prior, in particular immediately prior, to or at the time of administration to a patient in need thereof. In other embodiments, the contents of each bag may be administered separately to a patient, wherein two cell populations are used adjunctively in vivo.
The present invention also provides methods of mixing a population of stem or progenitor cells or cord blood including banked or cryopreserved cord blood with a population of embryonic-like stem cells. In one embodiment, the two populations are physically mixed. In another aspect of this embodiment, the two populations are physically mixed and then treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation. In another aspect of this embodiment, the stem cells and/or the embryonic-like stem cells are treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation and then physically mixed.
The present invention also provides methods of mixing a population of committed cells, e.g., a population of cells committed to differentiate into neurons, muscle cells, hematopoietic, vascular cells, adipocytes, chondrocytes, osteocytes, hepatocytes, pancreatic, or cardiac cells, with a population of embryonic-like stem cells. In one embodiment, the two populations are physically mixed. In another aspect of this embodiment, the two populations are physically mixed and then treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation. In another aspect of this embodiment, the committed cells and/or the embryonic-like stem cells are treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation and then physically mixed.
According to the methods of the invention, embryonic-like stem cells are extracted from a drained placenta by means of a perfusion technique that utilizes either or both of the umbilical artery and the umbilical vein. The placenta is preferably drained by exsanguination and collection of residual blood (e.g., residual umbilical cord blood). The drained placenta is then processed in such a manner as to establish the ex vivo, natural bioreactor environment in which the resident embryonic-like stem cells within the parenchyma and extravascular space are recruited. The embryonic-like stem cells migrate into the drained, empty microcirculation where, according to the methods of the invention, they are collected, preferable by washing into a collecting vessel by perfusion.
As disclosed above, a number of different pluripotent or multipotent stem cells can ’ be isolated from the perfused placenta at different time points during the perfusion, e.g.,
CD34+ /CD38+, CD34+ /CD38-, and CD34-/CD38- hematopoietic cells. In one embodiment, such cells may be used to supplement populations of stem cells, e.g., cord blood cells, according to the methods of the invention.
The present invention further provides an isolated homogenous population of human placental stem cells that has the potential to differentiate into all cell types. In another embodiment, the population of human placental stem cells has the potential to differentiate into one cell type. In yet another embodiment, the population of human placental stem cells has the potential to differentiate into several different cell types. Such cells may be used to supplement populations of stem cells, e.g., cord blood cells, according to the methods of the invention.
The present invention also provides methods of mixing a population of stem cells with a population of embryonic-like stem cells. In one embodiment, the two populations are physically mixed. In another aspect of this embodiment, the two populations are physically mixed and then treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation. In another aspect of this embodiment, the stem cells and/or the embryonic-like stem cells are treated with a growth factor, e.g., a cytokine and/or an interleukin, to induce cell differentiation and then physically mixed. In one embodiment, the mixed populations are treated with a growth factor to induce differentiation into a variety of cell types. In another embodiment, the mixed populations are treated with a growth factor to induce differentiation into a particular cell type. In another embodiment, the mixed populations are treated with a growth factor to prevent or suppress differentiation into a particular cell type. In certain embodiments, the culture conditions can be controlled, e.g., the mixed population of cells can be treated with a specific cocktail of cytokines or interleukins to direct or induce differentiation to a specific cell type.
The present invention provides pharmaceutical compositions that comprise populations of stem cells, e.g., cord blood cells, that have been supplemented with one or more populations of embryonic-like stem cells of the invention.
The invention also encompasses pharmaceutical compositions that comprise 2 5 populations of stem cells, e.g., cord blood cells, supplemented with one or more populations of cells that have high concentrations (or larger populations) of homogenous hematopoietic stem cells including, but not limited to, CD34+ /CD38- cells; and CD34-/ CD38- cells. One or more of these cell populations can be used with, or mixed with, cord blood hematopoietic cells, i.e., CD34+/CD38+ hematopoietic cells for transplantation and other uses.
According to the invention, populations of stem cells, e.g., umbilical cord blood, : supplemented with embryonic-like stem cells from the placenta have a multitude of uses, including therapeutic and diagnostic uses. The supplemented populations of stem cells can be used for transplantation or to treat or prevent disease. In one embodiment of the invention, the supplemented populations of cells are used to renovate and repopulate tissues and organs, thereby replacing or repairing diseased tissues, organs or portions thereof. In another embodiment, the supplemented populations of stem cells can be used as a diagnostic to screen for genetic disorders or a predisposition for a particular disease or disorder.
The present invention also provides methods of treating a patient in need thereof by administration of a population of stem cells supplemented with embryonic-like stem cells.
In one embodiment, the supplementation of the population of cord blood cells with embryonic-like stem cells occurs by mixing the stem cells and embryonic-like stem cells prior to administration of the supplemented population to the patient. In another embodiment, the supplementation of the population of stem cells with embryonic-like stem cells occurs upon administration of the supplemented population to the patient, e.g., by simultaneous administration of the cord blood cells and the embryonic-like stem cells. In another embodiment, the supplementation of the population of stem cells with embryonic- like stem cells occurs after administration of the cord blood cells to the patient, e.g., by administering the embryonic-stem cells separately from, and before or after, administration of the stem cells. | : 41. METHODS OF ISOLATING AND CULTURING PLACENTA 4.1. 1. Pretreatment of Placenta
According to the methods of the invention, a human placenta is recovered shortly after its expulsion after birth and, in certain embodiments, the cord blood in the placenta is recovered. In certain embodiments, the placenta is subjected to a conventional cord blood recovery process. Such cord blood recovery may be obtained commercially, e.g., LifeBank Inc., Cedar Knolls, N.J., ViaCord,
Cord Blood Registry and Cryocell. The cord blood can be drained shortly after expulsion of the placenta.
In other embodiments, the placenta is pretreated according to the methods disclosed in US
Publication No. 2003/0032179, filed February 13, 2002, which is incorporated herein by reference in its entirety. 41.2. Exsanguination of Placenta and Removal of Residual Cells
As disclosed in PCT publication WO 02/064755, published August 22, 2002, which is incorporated herein by reference in its entirety, the placenta after birth contains quiescent cells that can be activated if the placenta is properly processed after birth. For example, after expulsion from the womb, the placenta is exsanguinated as quickly as possible to prevent or minimize apoptosis.
Subsequently, as soon as possible after exsanguination the placenta is perfused to remove blood, ' residual cells, proteins, factors and any other materials present in the organ. Materials debris may also be removed from the placenta. Perfusion is normally continued with an appropriate perfusate for at least two to more than B } -13-
Amended sheet 29/11/2005 twenty-four hours. The placenta can therefore readily be used as a rich and abundant source of embryonic-like stem cells, which cells can be used for research, including drug discovery, treatment and prevention of diseases, in particular transplantation surgeries or therapies, and the generation of committed cells, tissues and organoids.
Further, surprisingly and unexpectedly, the human placental stem cells produced by the exsanguinated, perfused and/or cultured placenta are pluripotent stem cells that can readily be differentiated into any desired cell type.
According to the methods of the invention, stem or progenitor cells, including, but not limited to embryonic-like stem cells, may be recovered from a placenta that is exsanguinated, i.e., completely drained of the cord blood remaining after birth and/or a conventional cord blood recovery procedure. According to the methods of the invention, the methods for exsanguination of the placenta and removal of residual cells may be accomplished using any method known in the art, e.g., the methods disclosed in PCT publication WO 02/064755, published August 22, 2002, which is incorporated herein by reference in its entirety. 4.1.3. Culturing Placenta
After exsanguination and a sufficient time of perfusion of the placenta, the embryonic-like stem cells are observed to migrate into the exsanguinated and perfused microcirculation of the placenta where, according to the methods of the invention, they are collected, preferably by washing into a collecting vessel by perfusion. In other embodiments, the placenta is cultured, and the cells propagated are monitored, sorted and/or characterized according to the methods described in PCT publication WO 02/064755, published August 22, 2002, which is incorporated herein by reference in its entirety. 4.2. COLLECTION OF CELLS FROM THE PLACENTA
After exsanguination and perfusion of the placenta, embryonic-like stem cells migrate into the drained, empty microcirculation of the placenta where, according to the invention, they are collected, preferably by collecting the effluent perfusate in a collecting vessel.
In preferred embodiments, cells cultured in the placenta are isolated from the effluent perfusate using techniques known by those skilled in the art, such as, for example, density gradient centrifugation, magnet cell separation, flow cytometry, or other cell separation or sorting methods well known in the art, and sorted.
In a specific embodiment, the embryonic-like stem cells are collected from the placenta and, in certain embodiments, preserved, according to the methods described in
PCT publication WO 02/064755, published August 22, 2002, which is incorporated herein by reference in its entirety. 4.3. EMBRYONIC-LIKE STEM CELLS : 5 Embryonic-like stem cells obtained in accordance with the methods of the invention may include pluripotent cells, i.e., cells that have complete differentiation versatility, that are self-renewing, and can remain dormant or quiescent within tissue. The stem cells which may be obtained from the placenta include embryonic-like stem cells, multipotent cells, committed progenitor cells, and fibroblastoid cells.
The first collection of blood from the placenta is referred to as cord blood which contains predominantly CD34+ and CD38+ hematopoietic progenitor cells. Within the first twenty-four hours of post-partum perfusion, high concentrations of CD34+ and CD38- hematopoietic progenitor cells may be isolated from the placenta, along with high concentrations of CD34- and CD38+ hematopoietic progenitor cells. After about twenty- 15" four hours of perfusion, high concentrations of CD34- and CD38- cells can be isolated from the placenta along with the aforementioned cells. The isolated perfused placenta of the invention provides a source of large quantities of stem cells enriched for CD34+ and CD38- stem cells and CD34- and CD38+ stem cells. The isolated placenta which has been perfused for twenty-four hours or more provides a source of large quantities of stem cells enriched for CD34- and CD38- stem cells.
In a preferred embodiment, embryonic-like stem cells obtained by the methods of the invention are viable, quiescent, pluripotent stem cells that exist within a full-term human placenta and that can be recovered following successful birth and placental expulsion, resulting in the recovery of as many as one billion nucleated cells, which yield 50-100 million multipotent and pluripotent stem cells.
The human placental stem cells provided by the placenta are surprisingly embryonic-like, for example, the presence of the following cell surface markers have been identified for these cells: SSEA3-, SSEA4-, OCT-4+ and ABC-p*. Preferably, the embryonic-like stem cells of the invention are characterized by the presence of OCT-4+ and
ABC-p+ cell surface markers. Thus, the invention encompasses stem cells which have not been isolated or otherwise obtained from an embryonic source but which can be identified by the following markers: SSAE3-, SSAE4-, OCT-4+ and ABC-p+. In one embodiment, the human placental stem cells do not express MHC Class 2 antigens.
The stem cells isolated from the placenta are homogenous, and sterile. Further, the stem cells are readily obtained in a form suitable for administration to humans, i.e., they are of pharmaceutical grade.
Preferred embryonic-like stem cells obtained by the methods of the invention may be identified by the presence of the following cell surface markers: OCT-4+ and ABC-pt.
Further, the invention encompasses embryonic stem cells having the following markers:
CD10+, CD38-, CD29+, CD34-, CD44+, CDA45-, CD54+, CD90+, SH2+, SH3+, SH4+,
SSEA3-, SSEA4-, OCT-4+, and ABC-p+. Such cell surface markers are routinely determined according to methods well known in the art, e.g. by flow cytometry, followed by washing and staining with an anti-cell surface marker antibody. For example, to determine the presence of CD-34 or CD-38, cells may be washed in PBS and then double-stained with anti-CD34 phycoerythrin and anti-CD38 fluorescein isothiocyanate (Becton Dickinson,
Mountain View, CA).
In another embodiment, cells cultured in the placenta bioreactor are identified and characterized by a colony forming unit assay, which is commonly known in the art, such as
Mesen Cult™ medium (stem cell Technologies, Inc., Vancouver British Columbia)
The embryonic-like stem cells obtained by the methods of the invention may be induced to differentiate along specific cell lineages, including adipogenic, chondrogenic, osteogenic, hematopoietic, myogenic, vasogenic, neurogenic, and hepatogenic. In certain embodiments, embryonic-like stem cells obtained according to the methods of the invention are induced to differentiate for use in transplantation and ex vivo treatment protocols. In certain embodiments, embryonic-like stem cells obtained by the methods of the invention are induced to differentiate into a particular cell type and genetically engineered to provide a therapeutic gene product. In a specific embodiment, embryonic-like stem cells obtained by the methods of the invention are incubated with a compound ir vitro that induces it to differentiate, followed by direct transplantation of the differentiated cells to a subject. Thus, the invention encompasses methods of differentiating the human placental stem cells using standard culturing media. Further, the invention encompasses hematopoietic cells, neuron cells, fibroblast cells, strand cells, mesenchymal cells and hepatic cells.
Embryonic-like stem cells may also be further cultured after collection from the placenta using methods well known in the art, for example, by culturing on feeder cells, such as irradiated fibroblasts, obtained from the same placenta as the embryonic-like stem cells or from other human or nonhuman sources, or in conditioned media obtained from cultures of such feeder cells, in order to obtain continued long-term cultures of embryonic- like stem cells. The embryonic-like stem cells may also be expanded, either within the placenta before collection from the placental bioreactor or in vitro after recovery from the
Claims (114)
1. A composition comprising stem or progenitor cells and embryonic-like stem cells. . 5
2. A composition comprising umbilical cord blood cells and embryonic-like stem cells.
3. The composition of claim 1 that comprises a population of stem or progenitor cells and a population of embryonic-like stem cells.
4, The composition of claim 1 or 2 that is contained in a container.
5. The composition of claim 4 wherein the container is sealed, air tight, and sterile.
6. The composition of claim 1 or 2 wherein the stem or progenitor cells and embryonic-like stem cells are in contact with each other prior to or at the time of administration to a patient in need thereof.
7. The composition of claim 1 or 2 wherein stem or progenitor cells and embryonic-like stem cells are suitable for administration separately to a patient.
8. The composition of claim 1 or 2 that is suitable for bone marrow transplantation.
9. The composition of claim 1 or 2 that is suitable for administration in humans.
10. The composition of claim 1 or 2 wherein the stem or progenitor cells are from umbilical cord blood or placental blood, fetal or neonatal hematopoietic stem or progenitor cells, human stem cells, adult cells or bone marrow stem or progenitor cells.
11. The composition of claim 10 wherein the stem or progenitor cells are fetal or neonatal hematopoietic stem or progenitor cells.
12. The composition of claim 11 wherein a plurality of the hematopoietic stem or progenitor cells express the cell surface markers CD34+ and CD38-.
13. The composition of claim 10 wherein the stem or progenitor cells are umbilical cord blood stem cells.
14. The composition of claim 13 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38-.
15. The composition of claim 13 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38+.
16. The composition of claim 1 or 2 wherein the embryonic-like stem cells exhibit at least one of the following cell surface markers: CD10, CD29, CD44, CD54, CD90, SH2, SH3, SH4, OCT-4 or ABC-p, or lacks at least one of the following cell surface markers: CD34, CD45, SSEA3, SSEA4.
17. The composition of claim 16 wherein the embryonic-like stem cells are OCT-4+ and ABC-p+.
18. The composition of claim 16 wherein the embryonic-like stem cells are SSEA3- and SSEA4-.
19. AKkit comprising a composition of claim 1 or 2 wherein said stem or progenitor cells are in a first container and said embryonic-like stem cells are in a second container.
20. A method of preparing a composition comprising a plurality of stem or progenitor cells and a plurality of embryonic-like stem cells which comprises isolating and contacting the plurality of stem cells with the plurality of embryonic-like stem cells.
21. The method of claim 20 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells is each contained in a separate container prior to mixing.
22. The method of claim 20 wherein the composition 1s suitable for administration in humans.
23. The method of claim 20 wherein the stem or progenitor cells are from umbilical cord blood or placental blood, fetal or neonatal hematopoietic stem or progenitor cells, human stem cells, adult cells or bone marrow stem or progenitor cells.
24. The method of claim 20 wherein the stem or progenitor cells are fetal or neonatal hematopoietic stem or progenitor cells.
25. The method of claim 20 wherein a plurality of the hematopoietic stem or progenitor cells express the cell surface markers CD34+ and CD38-.
26. The method of claim 20 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells are physically mixed.
27. Use of a composition including a plurality of stem or progenitor cells and a plurality of embryonic-like stem cells in the manufacture of a medicament for the treatment of a patient in need thereof .
28. The use of claim 27 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells is each contained in a separate container prior to mixing.
29. The use of claim 27 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells are in contact with each other prior to or at the time of administration to a patient in need thereof.
30. The use of claim 27 wherein the stem or progenitor cells and embryonic-like stem cells are suitable for bone marrow transplantation.
31. The use of claim 27 wherein the stem or progenitor cells and embryonic-like stem cells are suitable for administration to a human.
32. The use of claim 27 wherein the stem or progenitor cells are from umbilical cord blood or placental blood, fetal or neonatal hematopoietic stem or progenitor cells, human stem cells, adult cells or bone marrow stem or progenitor cells.
33. The use of claim 32 wherein the stem or progenitor cells are fetal or neonatal hematopoietic stem or progenitor cells. -54 Amended sheet 29/11/2005
34. The use of claim 33 wherein a plurality of the hematopoietic stem or progenitor cells express the cell surface markers CD34+ and CD38-.
35. The use of claim 32 wherein the stem or progenitor cells are umbilical cord blood stem cells.
36. The use of claim 35 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38§-.
37. The use of claim 35 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38+.
38. The use of claim 27 wherein the embryonic-like stem cells exhibit at least one of the following cell surface markers: CD10+, CD29+, CD34-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+ and ABC-p+.
39. The use of claim 38 wherein the embryonic-like stem cells are OCT-4+ and ABC-p+.
40. The use of claim 38 wherein the embryonic-like stem cells are SSEA3- and SSEA4-.
41. The use of claim 27 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells are mixed prior to or at the time of administration to a patient in need thereof.
42, The use of claim 27 wherein the plurality of stem or progenitor cells and the plurality of embryonic-like stem cells are physically mixed.
43. The use of claim 27 wherein the plurality of stem or progenitor cells and/or the plurality of embryonic-like stem cells is treated with a growth factor to induce differentiation into a particular cell type.
44. The use of claim 27 wherein the plurality of stem or progenitor cells and/or the plurality of embryonic-like stem cells is treated with a growth factor to prevent or suppress differentiation nto a particular cell type.
45. Use of a composition including a plurality of umbilical cord blood cells and a plurality of embryonic-like stem cells in the manufacture of a medicament for the treatment of a patient in need thereof.
46. The use of claim 45 wherein the plurality of umbilical cord blood cells and the plurality of embryonic-like stem cells is each contained in a separate container prior to mixing. - 55 Amended sheet 29/11/2005
47. The use of claim 45 wherein the plurality of umbilical cord blood cells and the plurality of embryonic-like stem cells are in contact with each other prior to or at the time of administration to a patient in need thereof.
48. The use of claim 45 wherein the plurality of umbilical cord blood cells and the plurality of embryonic-like stem cells are suitable for administration separately to a patient.
49. The use of claim 45 wherein the umbilical cord blood cells are fetal or neonatal hematopoietic stem or progenitor cells.
50. The use of claim 49 wherein a plurality of the hematopoietic stem or progenitor cells express the cell surface markers CD34+ and CD38-.
51. The use of claim 45 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38-.
52. The use of claim 45 wherein a plurality of the umbilical cord blood stem cells express the cell surface markers CD34+ and CD38+.
53. The use of claim 45 wherein the embryonic-like stem cells exhibit at least one of the following cell surface markers: CD10+, CD29+, CD34-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+ and ABC-p+.
54. The use of claim 53 wherein the embryonic-like stem cells are OCT-4+ and ABC-p+.
SS. The use of claim 53 wherein the embryonic-like stem cells are SSEA3- and SSEA4-.
56. The use of claim 45 wherein the plurality of umbilical cord blood stem cells and the plurality of embryonic-like stem cells are mixed prior to or at the time of administration to a patient in need thereof.
57. The use of claim 45 wherein the plurality of umbilical cord blood stem cells and the plurality of embryonic-like stem cells are physically mixed.
58. The use of claim 45 wherein the plurality of umbilical cord blood stem cells and/or the plurality of embryonic-like stem cells is treated with a growth factor.
59. The use of claim 58 wherein the plurality of umbilical cord blood stem cells and/or ) the plurality of embryonic-like stem cells is treated with the growth factor to induce differentiation into a particular cell type. : -56— Amended sheet 29/11/2005
60. The use of claim 58 wherein the plurality of umbilical cord blood stem cells and/or the plurality of embryonic-like stem cells is treated with the growth factor to prevent or suppress differentiation into a particular cell type.
61. The use of claim 45 wherein said patient has a disease, disorder or condition that includes an inflammation component.
62. The use of claim 45 wherein said patient has a vascular disease, disorder or condition.
63. The use of claim 62 wherein said disease, disorder or condition is atherosclerosis.
64. The use of claim 45 wherein said patient has a neurological disease, disorder or condition.
65. The use of claim 64, wherein said disease, disorder or condition is selected from the group consisting of amylotrophic lateral sclerosis and multiple sclerosis.
66. The use of claim 45, wherein said patient has an autoimmune disorder.
67. The use of claim 66 wherein said autoimmune disorder is selected from the group consisting of diabetes and amylotrophic lateral sclerosis.
68. The use of claim 45, wherein said patient has a condition that is caused by or associated with trauma or injury.
69. The use of claim 68, where said trauma or injury is trauma or injury to the central nervous system.
70. The use of claim 68, wherein said trauma or injury 1s trauma or injury to the peripheral nervous system.
71. Use of a composition including umbilical cord blood cells, or stem cells isolated therefrom, and embryonic-like stem cells in the manufacture of a medicament for the treatment of myelodysplasia.
72. The use of claim 71 wherein the administration of the umbilical cord blood cells, or stem cells isolated therefrom, and the administration of the embryonic-like stem cells is concurrent.
73. The use of claim 71 wherein the umbilical cord blood cells, or stem cells isolated therefrom, and the embryonic-like stem cells are combined before administration. -57 — Amended sheet 29/11/2005
74. Use of a composition including umbilical cord blood cells, or stem cells isolated therefrom, and embryonic-like stem cells in the manufacture of a medicament for the transplantation of hematopoietic progenitor cells for the treatment or prevention of disease.
75. The use of claim 74 wherein the administration of the umbilical cord blood cells, or stem cells isolated therefrom, and the administration of the embryonic-like stem cells is concurrent.
76. The use of claim 74 wherein the umbilical cord blood cells, or stem cells isolated therefrom, and the embryonic-like stem cells are combined before administration.
77. A composition which comprises stem or progenitor cells from umbilical cord blood supplemented with a plurality of embryonic-like stem cells.
78. Use of a composition including at least 5 x 10° nucleated cells, said at least 5 x 10° nucleated cells comprising embryonic-like stem cells, in the manufacture of a medicament for the treatment of a patient in need thereof.
79. The use of claim 78 wherein said embryonic-like stem cells are contained in a container.
80. The use of claim 78 wherein said embryonic-like stem cells are suitable for administration to a patient.
81. The use of claim 78 wherein said embryonic-like stem cells are suitable for bone marrow transplantation.
82. The use of claim 78 wherein said embryonic-like stem cells are suitable for administration in humans.
83. The use of claim 78 wherein the embryonic-like stem cells exhibit at least one of the following cell surface markers: CD10+, CD29+, CD34-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+ and ABC-p+.
84. The use of claim 83 wherein the embryonic-like stem cells are OCT-4+ and ABC-p+.
85. The use of claim 83 wherein the embryonic-like stem cells are SSEA3- and SSEA4-.
86. The use of claim 78 wherein the embryonic-like stem cells are treated with a growth factor. -58— Amended sheet 29/11/2005
[} i .
87. The use of claim 86 wherein the growth factor is a cytokine, lymphokine, interferon, colony stimulating factor (CSF), interferon, chemokine, interleukin, human hematopoietic growth factor, hematopoietic growth factor ligand, stem cell factor, thrombopoeitin (Tpo), granulocyte colony-stimulating factor (G-CSF), leukemia inhibitory factor, basic fibroblast growth factor, placenta derived growth factor or epidermal growth factor.
88. The use of claim 87 wherein the embryonic-like stem cells are treated with the growth factor to induce differentiation into a plurality of cell types.
89. The use of claim 87 wherein the plurality of embryonic-like stem cells is treated with the growth factor to prevent or suppress differentiation into a particular cell type.
90. The use of claim 78 wherein said treating comprises administering at least 10 x 10° total nucleated cells.
91. The use of claim 78 wherein said treating comprises administering at least 20 x 10° total nucleated cells.
92. The use of claim 27, wherein at least 30% of said cells in said composition are embryonic-like stem cells.
93. The use of claim 27, wherein at least 60% of said cells in said composition are embryonic-like stem cells.
94. The use of claim 78 wherein said patient has a disease, disorder or condition that includes an inflammation component.
95. The use of claim 78 wherein said patient has a vascular disease, disorder or condition.
96. The use of claim 95 wherein said disease, disorder or condition is atherosclerosis.
97. The use of claim 78 wherein said patient has a neurological disease, disorder or condition.
98. The use of claim 97, wherein said disease, disorder or condition is selected from the group consisting of amylotrophic lateral sclerosis and multiple sclerosis. ’
99. The use of claim 78, wherein said patient has an immune-related disorder.
100. The use of claim 99 wherein said autoimmune disorder is selected from the group consisting of allergies, diabetes and amylotrophic lateral sclerosis. -50_ Amended sheet 29/11/2005
4 rN
101. The use of claim 78, wherein said patient has a condition that is caused by or associated with trauma or injury.
102. The use of claim 101, where said trauma or injury is trauma or injury to the central nervous system.
103. The use of claim 101, wherein said trauma or injury is trauma or injury to the peripheral nervous system.
104. The use of claim 78, wherein said at least 5 x 10° nucleated cells comprises a pool of cells derived from a plurality of donors.
105. The use of claim 78 wherein none of said cells in said at least 5 x 10° nucleated cells 1s HLA-typed prior to said administration.
106. The use of claim 78 wherein said at least 5 x 10° nucleated cells is preconditioned for between 18 hours and 21 days prior to said administration.
107. The use of claim 78 wherein said at least 5 x 10° nucleated cells is preconditioned for between 48 hours and 10 days prior to said administration.
108. The use of claim 78, wherein said at least 5 x 10° nucleated cells is preconditioned for between 3-5 days prior to said administration.
109. A composition including umbilical cord blood cells, or stem cells isolated therefrom, and embryonic-like stem cells for use in treating myelodysplasia.
110. A composition including umbilical cord blood cells, or stem cells isolated therefrom, and embryonic-like stem cells for use in a method for transplanting hematopoietic progenitor cells for the treatment or prevention of disease.
111. A composition according to claim 1 substantially as herein described with reference to any one of the illustrative examples.
112. A composition according to claim 2 substantially as herein described with reference to any one of the illustrative examples.
113. A method according to claim 20 substantially as herein described with reference to any one of the illustrative examples. - 60 — Amended sheet 29/11/2005
BR WO 03/068937 PCT/US03/04539
114. A composition according to claim 77 substantially as herein described with reference to any one of the illustrative examples. / -61-— Amended sheet 29/11/2005
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| US20030032179A1 (en) * | 2000-12-06 | 2003-02-13 | Hariri Robert J. | Post-partum mammalian placenta, its use and placental stem cells therefrom |
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| KR101176146B1 (en) | 2012-08-22 |
| IL207763A0 (en) | 2010-12-30 |
| AU2008249204A1 (en) | 2008-12-18 |
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