US20160082048A1 - Pluripotent stem cell for treatment of cerebral infarction - Google Patents
Pluripotent stem cell for treatment of cerebral infarction Download PDFInfo
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
- A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
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Definitions
- the present invention relates to a cell preparation used in regenerative medicine. More specifically, the present invention relates to a cell preparation containing pluripotent stem cells that are effective for repairing and regenerating brain tissue that has been damaged by cerebral infarction.
- Cerebral infarction refers to a brain dysfunction that occurs due to ischemic necrosis localized in the brain, requires emergency treatment, and is one of the three leading causes of death after cancer and heart disease.
- cerebral infarction is categorized as thrombotic, embolic or hemodynamic cerebral infarction, or is classified into categories such as atherothrombotic cerebral infarction, cardiogenic embolism or lacunar infarction from the perspective of clinical findings.
- Ischemia occurs due to a local interruption of cerebral blood flow caused by a cerebrovascular lesion such as arteriosclerosis or cardiogenic thromboembolism, and nerve cell death is induced at the ischemic core due to energy depletion.
- a cerebrovascular lesion such as arteriosclerosis or cardiogenic thromboembolism
- nerve cell death is induced at the ischemic core due to energy depletion.
- blood flow remains by means of collateral circulation, and although nerve cells are not functioning in terms of electrophysiology, they remain in a viable state. Nerve cells in this area eventually end up undergoing necrosis unless treatment is performed, and in pathological terms, the infracted area progresses and clinically results in the disorder of cerebral dysfunction. Accordingly, cerebral dysfunction can be treated provided the function of nerve cells in the affected area can be restored as quickly as possible.
- This reversible region of incomplete ischemia is referred to as the penumbra.
- the purpose of treating the acute stage of cerebral infarction is to restore the function of nerve cells in this penumbra region, and the outcome thereof is dependent upon the degree of ischemia and its duration. Namely, outcome is determined by how quickly blood flow can be resumed to the penumbra region. Nerve cells in this penumbra region are believed to be able to survive for 3 to 6 hours following an attack. In addition, the allowed amount of time during which the function of nerve cells in a penumbra region can be restored by treatment is referred to as treatment time (Stroke, Vol. 21, p. 637-676 (1990)).
- thrombolytic therapy using recombinant human plasminogen activator which has been approved in the U.S. for use in the treatment of acute stage cerebral infarction, was developed for the purpose of restoring blood flow to a penumbra region by lysing thrombi causing ischemia.
- rt-PA recombinant human plasminogen activator
- rt-PA is thought to improve dysfunction caused by cerebral infarction by enabling resumption of the supply of blood to an ischemic region and inhibiting the progression of cerebral infarction by lysing thrombi.
- This result indicated that early resumption of cerebral blood flow by thrombolytic action improves long-term prognosis (N. Eng. J. Med., Vol. 333, p. 1581-1587 (1995)).
- stem cell therapy is expected to be a new treatment method used in the treatment of cerebral infarction in addition to using thrombolytic therapy as described above, it has yet to demonstrate adequate therapeutic effects and is currently not established as a treatment method (Sinden, J. D. & Muir, K. W., Vol. 7, p. 426-434 (2012)).
- Muse cells multilineage-differentiating stress enduring cells
- SSEA-3 stage-specific embryonic antigen-3
- Muse cells were also determined to be able to be concentrated by stimulating mesenchymal cell fractions with various types of stress (WO2011/007900; Kuroda, Y., et al., Proc. Natl. Acad. Sci. USA, Vol.
- An object of the present invention is to provide a novel medical application to regenerative medicine that uses pluripotent stem cells (Muse cells). More specifically, an object of the present invention is to provide a cell preparation for prevention and/or treatment of cerebral infarction and sequelae occurring in association therewith (including movement impairment, sensory impairment and speech impairment) that contains Muse cells.
- Muse cells pluripotent stem cells
- the inventors of the present invention found that, by injecting Muse cells into the cerebral parenchyma of a rat cerebral infarction model induced by ischemia-reperfusion by inserting an embolus into a cerebral blood vessel, the Muse cells survive over the course of several months after taking to damaged brain tissue and bring about a reduction in infarct size along with improvement or restoration of brain function as a result of spontaneously differentiating into brain cells, thereby leading to completion of the present invention.
- a cell preparation for treating cerebral infarction containing pluripotent stem cells positive for SSEA-3 isolated from biological mesenchymal tissue or cultured mesenchymal cells.
- pluripotent stem cells are pluripotent stem cells having all of the properties indicated below:
- pluripotent stem cells have the ability to differentiate into one or more cells selected from the group consisting of nerve cells, glial cells, vascular endothelial cells, and/or microglial cells.
- the present invention is able to dramatically reduce infarct size by a mechanism involving regeneration of brain tissue in which Muse cells differentiate cells that compose brain tissue in damaged brain tissue by being administered to the cerebral parenchyma of a subject suffering from cerebral infarction.
- FIG. 1 indicates the results of evaluating neurological severity score (NSS) over the course of three months following injection of Muse cells derived from human skin fibroblasts, human skin fibroblasts from which Muse cells had been removed (namely, non-Muse cells) or phosphate-buffered saline (PBS) into the cerebral parenchyma of a rat cerebral infarction model.
- NSS neurological severity score
- PBS phosphate-buffered saline
- FIG. 2 indicates the results of a Rotarod performance test of motor function in a rat cerebral infarction model injected with Muse cells, non-Muse cells or phosphate-buffered saline (PBS). Recovery of motor function was observed over time based on the percentage of the average value of measured values (two) obtained on two measurement days by using two measured values obtained prior to transplant of Muse cells and the like as a baseline.
- PBS phosphate-buffered saline
- FIG. 3 indicates the results of measuring somatosensory evoked potential (SEP) in a rat cerebral infarction model 85 days after injecting Muse cells and the like.
- SEP somatosensory evoked potential
- FIG. 4 indicates fluorescent images indicating taking and differentiation of Muse cells in brain tissue.
- Human-derived Muse cells were labeled green with human mitochondria marker, while nerve cells were labeled red using ⁇ -tubulin III as a marker.
- Muse cells injected into cerebral parenchyma were suggested to accumulate in a region bordering the infarction and differentiate into nerve cells after taking to that region. On the other hand, taking and differentiation of non-Muse cells were not observed.
- FIG. 5 indicates the results of observing human mitochondria marker-positive cells under a fluorescence microscope and respectively counting the number of cells contained in ten fields. Although hardly any non-Muse cells took to a region bordering the infarction, numerous Muse cells were present at that site.
- the present invention relates to a cell preparation for treating cerebral infarction that contains SSEA-3-positive pluripotent stem cells (Muse cells).
- SSEA-3-positive pluripotent stem cells Mal cells
- the present invention aims to treat cerebral infarction using a cell preparation containing SSEA-3-positive pluripotent stem cells (Muse cells).
- Cerebral infarction is a state that ischemic area is locally generated in brain by obstruction or perfusion pressure decrease of cerebral blood vessel whereby an irreversible necrosis of neurons occurs. It is preferably an acute brain infarction phase within 48 hours of the infarction onset, more preferably within 24 hours, still more preferably within 6 hours and, most preferably, cerebral infraction within 3 hours of the infraction onset.
- onset is defined as the time that which the patient was last seen in a normal state, or bedtime for unwitnessed cerebral infraction occurring during the night.
- cerebral infarction is classified into cerebral thrombus and cerebral embolism and the present invention is useful for the therapy of cerebral thrombus and cerebral embolism.
- the term “therapy of cerebral infraction” means an effect of preventing the progress of infarct foci in an acute phase of cerebral infraction, an effect of improving the dysfunction or the subjective symptom accompanied by cerebral infarction and/or an effect of preventing the occurrence of psychiatric symptom and convulsion onset during a chronic phase. It further includes prevention of recurrence of the onset of cerebral infraction.
- degree of cerebral infarction may be classified depending upon infarct size, extent of infarct foci (penetrating branch and cortical branch), side of infarct (left, right or both), region of infarct (anterior cerebral artery region, middle cerebral artery region, posterior cerebral artery region, watershed region, brain stem, cerebellum and others) and degree of edema.
- suppression of the progress of cerebral infarction means an effect that expansion of infarct nidus with a lapse of time after the onset of ischemic event is suppressed as compared with the untreated case.
- reducing effect of cerebral infarction means that the volume of infract foci generated by cerebral infarction, which was measured prior to administration of the cell preparation according to the present invention, is reduced at an evaluation point after a certain period of time following the administration of the cell preparation.
- the cell preparation according to the present invention can be used in prevention and/or treatment of sequelae from cerebral infarction.
- “sequelae” includes speech and language disorder, disturbance of perception such as numbness, disorder of movement in a limb, headache, vomiting, visual loss, deglutition disorder, articulation disorder, dementia and the like.
- Muse cells can be obtained from bone marrow, adipose tissue (Ogura, F., et al., Stem Cells Dev., Nov. 20, 2013 (Epub) (published on Jan. 17, 2014), or skin tissue such as dermal connective tissue, and are sporadically present in the connective tissue of various organs.
- Muse cells or cell populations containing Muse cells can be isolated from body tissue, for example, by using these antigen markers as indicators. Details regarding methods used to isolate and identify Muse cells as well as their characteristics are disclosed in International Publication No. WO2011/007900. In addition, as has been reported by Wakao, et al.
- Muse cells in the case of using a cell culture obtained by culturing mesenchymal cells present in bone marrow, skin and the like as the parent population of Muse cells, all cells positive for SSEA-3 are known to be positive for CD105.
- Muse cells in the case of isolating Muse cells from biological mesenchymal tissue or cultured mesenchymal cells, Muse cells can be purified and used simply by using SSEA-3 as an antigen marker.
- pluripotent stem cells able to be used in a cell preparation for treating cerebral infarction (including sequelae) that have been isolated from biological mesenchymal tissue or cultured mesenchymal cells by using SSEA-3 as an antigen marker, or a cell population containing Muse cells, may simply be described as “SSEA-3-positive cells”.
- non-Muse cells means cells included in biological mesenchymal tissue or cultured mesenchymal cells, which are not “SSEA-3-positive cells.”
- Muse cells or cell populations containing Muse cells can be isolated from biological tissue (such as mesenchymal tissue) using antibody to the cell surface marker SSEA-3 alone or using antibody to SSEA-3 and CD105, respectively.
- biological tissue refers to the biological tissue of a mammal. In the present invention, although an embryo in a development stage prior to a fertilized egg or blastula stage is not included in biological tissue, an embryo in a development stage in or after the fetus or blastula stage, including the blastula, is included.
- mammals include, but are not limited to, primates such as humans or monkeys, rodents such as mice, rats, rabbits or guinea pigs as well as cats, dogs, sheep, pigs, cows, horses, donkeys, goats and ferrets.
- the Muse cells used in the cell preparation of the present invention are clearly distinguished from embryonic stem (ES) cells and embryonic germ (EG) cells in that they are directly collectable from biological tissue and are non-tumorigenic.
- ES embryonic stem
- EG embryonic germ
- meenchymal tissue refers to tissue such as bone, synovial membrane, fat, blood, bone marrow, skeletal muscle, dermis, ligaments, tendons, tooth pulp, umbilical cord, umbilical cord blood, as well as tissues present in various organs.
- Muse cells can be obtained from bone marrow, skin or fat tissue.
- Muse cells are preferably used that have been isolated from mesenchymal tissue collected from the living body.
- Muse cells may also be isolated from cultured mesenchymal cells such as fibroblasts or bone mallow mesenchymal cells using the aforementioned isolation means.
- Muse cells used in the cell preparation of the present invention may be autologous or allogenic relative to the recipient who receives the cell transplant.
- Muse cells or cell populations containing Muse cells can be isolated from biological tissue by using their property of being SSEA-3-positive and CD105-positive, human adult skin is known to contain various types of stem cells and precursor cells.
- Muse cells are not the same as these cells.
- stem cells and precursor cells include skin-derived precursor (SKP) cells, neural crest stem cells (NCSC), melanoblasts (MB), perivascular cells (PC), endothelial precursor (EP) cells and adipose-derived stem cells (ADSC).
- SFP skin-derived precursor
- NSC neural crest stem cells
- MB melanoblasts
- PC perivascular cells
- EP endothelial precursor
- ADSC adipose-derived stem cells
- Muse cells can be isolated by using non-expression of at least one of 11 markers, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 markers, selected from the group consisting of CD34 (marker for EP and ADSC), CD117 (c-kit) (MB marker), CD146 (PC and ADSC marker), CD271 (NGFR) (NCSC marker), NG2 (PC marker), vWF factor (von Willebrand factor) (EP marker), Sox10 (NCSC marker), Snail (SKP marker), Slug (SKP marker), Tyrp1 (MB marker) and Dct (MB marker).
- 11 markers such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 markers, selected from the group consisting of CD34 (marker for EP and ADSC), CD117 (c-kit) (MB marker), CD146 (PC and ADSC marker), CD271 (NGFR) (NCSC marker), NG2 (PC marker), vWF factor (von Willebrand factor) (EP marker), Sox10 (NCSC marker), Snail (SK
- Muse cells can be isolated by using non-expression of CD117 and CD146 as an indicator, can be isolated using non-expression of CD117, CD146, NG2, CD34, vWF and CD271 as an indicator, and can be isolated by using non-expression of the aforementioned 11 markers as an indicator.
- Muse cells having the aforementioned characteristics used in the cell preparation of the present invention may have at least one property selected from the group consisting of:
- the Muse cells used in the cell preparation of the present invention have all of the aforementioned properties.
- “low or absent telomerase activity” refers to telomerase activity being low or being unable to be detected in the case of having detected telomerase activity using, for example, the Trapeze XL Telomerase Detection Kit (Millipore Corp.).
- “Low” telomerase activity refers to having telomerase activity roughly equal to that of human fibroblasts, for example, or having telomerase activity that is 1 ⁇ 5 or less and preferably 1/10 or less in comparison with Hela cells.
- Muse cells have the ability to differentiate into the three germ layers (endoderm, mesoderm and ectoderm) in vitro and in vivo, and by inducing to differentiate by culturing in vitro, for example, can differentiate into skin, liver, nerve, muscle, bone or fat and the like.
- Muse cells may also demonstrate the ability to differentiate into the three germ layers in the case of transplanting in vivo into testes, for example.
- Muse cells also have the ability to migrate, graft and differentiate into a damaged organ (such as the heart, skin, spinal cord, liver or muscle) by being transplanted into the body by intravenous injection.
- Muse cells proliferate in a suspension culture, they have the property of discontinuing proliferation for about 10 ⁇ 14 days. In adherent culture, their doubling time is approximately 1.3 days/cell division which is similar to human fibroblasts, and keep proliferating until cell reach nearly to Heyflick limit. Thus, in the case of having been transplanted into testes, have the property of not becoming malignant for at least six months.
- Muse cells have self-renewal (self-replication) ability.
- self-renewal refers to culturing cells contained in an embryoid body-like cell mass obtained by suspension culturing single Muse cell and allowing them to reform an embryoid body-like cell mass from a single cell again as well as to demonstrate spontaneous differentiation of embryoid body-like cell mass into triploblastic cell lineages on gelatin coated culture. Self-renewal may be carried out for one cycle or repeated for a plurality of cycles.
- the cell preparation of the present invention is obtained by suspending Muse cells or a cell population containing Muse cells obtained in the aforementioned (1) in physiological saline or a suitable buffer (such as phosphate-buffered physiological saline).
- physiological saline or a suitable buffer such as phosphate-buffered physiological saline.
- cells may be cultured prior to cell transplant and allowed them to proliferate until a prescribed cell concentration is obtained.
- Muse cells do not undergo neoplastic transformation, there is little likelihood of the cells becoming malignant even if cells recovered from biological tissue are contained that have still not differentiated, thereby making them safe.
- culturing of recovered Muse cells can be carried out in an ordinary growth medium (such as minimum essential medium- ⁇ ( ⁇ -MEM) containing 10% bovine calf serum). More specifically, a solution containing a prescribed concentration of Muse cells can be prepared by selecting media, additives (such as antibiotics and serum) and the like suitable for the culturing and proliferation of Muse cells with reference to the aforementioned International Publication No. WO2011/007900.
- an ordinary growth medium such as minimum essential medium- ⁇ ( ⁇ -MEM) containing 10% bovine calf serum.
- DMSO dimethylsulfoxide
- serum albumin for protecting the cells, or antibiotics and the like for preventing contamination and growth of bacteria
- other pharmaceutically allowable components such as a carrier, vehicle, disintegrating agent, buffer, emulsifier, suspending agent, soothing agent, stabilizer, storage agent, preservative or physiological saline
- cells or components other than Muse cells contained in mesenchymal cells may also be contained in the cell preparation.
- a person with ordinary skill in the art is able to add these factors and pharmaceutical agents to a cell preparation at suitable concentrations. In this manner, Muse cells can be used in the form of a pharmaceutical composition containing various types of additives.
- the number of Muse cells contained in the cell preparation prepared in the manner described above can be suitably adjusted in consideration of the gender, age and body weight of the subject, disease state and state in which the cells are used so as to obtain the desired effect in treatment of cerebral infarction and sequelae (such as suppression of the progress of cerebral infarction, reduction of cerebral infarction volume, restoration of motility function, restoration of speech and language function, restoration of perceptual function).
- cerebral infarction and sequelae such as suppression of the progress of cerebral infarction, reduction of cerebral infarction volume, restoration of motility function, restoration of speech and language function, restoration of perceptual function.
- a rat model of cerebral infarction was produced using an embolus, and various types of effects of transplanting Muse cells were examined. Extremely superior effects were obtained by administering SSEA3-positive cells to Wistar rats weighing about 200 to 300 g at 3 ⁇ 10 4 cells/animal.
- the cell preparation of the present invention may be administered a plurality of times (such as 2 to 10 times) at a suitable interval (such as twice per day, once per day, twice per week, once per week, once every two weeks, once every one month, one every two months, once every six months) until the desired therapeutic effect is obtained.
- the therapeutically effective dose is preferably administered, for example, 1 to 10 times at 1 ⁇ 10 3 cells to 2 ⁇ 10 7 cells per individual.
- examples of total individual doses include 1 ⁇ 10 3 cells to 2 ⁇ 10 8 cells, 1 ⁇ 10 4 cells to 1 ⁇ 10 8 cells, 2 ⁇ 10 4 cells to 5 ⁇ 10 7 cells, 5 ⁇ 10 4 cells to 2 ⁇ 10 7 cells and 1 ⁇ 10 5 cells to 1 ⁇ 10 7 cells.
- a rat cerebral infraction model can be constructed and used to examine the therapeutic effects of the cell preparation of the present invention on cerebral infarction (including sequelae).
- rats of this model typical examples thereof include Wistar rats and Spraque-Dawley rats.
- a cerebral infarction model can be created in order to promote symptoms resembling human cerebral infarction by inserting an embolus from the carotid artery of the rat, occluding the artery (such as the middle cerebral artery) leading to the brain tissue where cerebral infarction is to be induced for a prescribed amount of time with the embolus (to induce an ischemic state), and then extracting the embolus.
- the status of the cerebral infarction can be confirmed with a brain tissue section (following TTC staining).
- the cell preparation of the present invention has a heterologous relationship with the rats administered with the preparation since the Muse cells are of human origin.
- an immunosuppressant such as cyclosporin
- the cell preparation of the present invention is able to restore or return to normal brain function in patients suffering from cerebral infarction or patients suffering from sequelae thereof.
- restoration of brain function refers to alleviation and inhibition of the progression of various functional disorders (including sequelae) accompanying cerebral infarction, and preferably refers to alleviation of functional disorders to a degree that they do not present a problem during the course of daily life.
- returning of brain function to normal refers to returning functional disorders (including sequelae) to the state prior to the onset of cerebral infarction.
- evaluation of restoration of brain function is typically carried out by electrophysiological studies, neurological severity scores (NSS), imaging examinations and pathology studies.
- “electrophysiological studies” refer to studies performed to carry out functional evaluations of various organs, including the brain, by observing a potential (waveform of an electrical signal) in response to an electrical stimulus with a prescribed apparatus in order to evaluate the function of the central nervous system, peripheral nervous system, muscle and the like.
- a potential waveform of an electrical signal
- peripheral nervous system a prescribed apparatus in order to evaluate the function of the central nervous system, peripheral nervous system, muscle and the like.
- SEP somatosensory evoked potential
- the study consists of an examination for measuring the potential induced when a response induced by sensory stimulation of the limbs passes through a sensory pathway and is transmitted to the cerebral cortex.
- the degree of functional recovery of the central nervous system of a patient can be confirmed objectively following administration of the cell preparation of the present invention to the patient.
- the neurological severity score is used to evaluate the degree of function of a damaged portion of the brain by scoring each parameter.
- An NSS for use in rats has been indicated by Chen, J. et al. (Stroke, Vol. 32, p. 1005-1111 (2001)).
- a rat cerebral infarction model was prepared by inserting an embolus from the carotid artery of Wistar rats (males, age 10 weeks) and occluding a portion of the cerebral blood vessels (such as the middle carotid artery (MCA)). Subsequently, the embolus was extracted, the vessel was reperfused, and the rats were then used in the following experiments as a cerebral infarction model.
- MCA middle carotid artery
- the cerebral infarction rats prepared in Example 1 were divided into three groups, and Muse cells (1 ⁇ 10 4 cells, 2 ⁇ l PBS at 3 locations), non-Muse cells (1 ⁇ 10 4 cells, 2 ⁇ l PBS at three locations) or physiological saline (6 ⁇ l) were injected directly into the cerebral parenchyma on day 2 following reperfusion. Subsequently, improvement of rat motor function was evaluated over time and cell kinetics were analyzed after a prescribed amount of time.
- NSS neurological severity score
- evaluations were carried out on the following parameters consisting of: standing up with the tail (one point for each parameter (maximum of 3 points)), state when lying on the floor (0 to 3 points), sensory test (1 or 2 points), beam balance test (0 to 6 points) and reflex absence/motor impairment (maximum of 4 points).
- scores decreased for about the first ten days after which scores tended to be maintained at 6 to 8 points.
- scores on day 20 were significantly lower in comparison with the other groups, and the scores tended to decrease further at the time the experiment was completed (80 days and beyond), with significant differences observed in comparison with the other groups.
- Somatosensory evoked potential was measured in the rat cerebral infarction model 85 days after injection of Muse cells and the like ( FIG. 3 ).
- the straight muscle of the thigh was stimulated at 10 mA and 1 Hz 100 times (at 1 second intervals), and potential was measured at a location 2.5 mm to the side and 2.5 mm posterior to the bregma at a depth of 1 mm.
- Right brain-left leg (rt-lt) indicates the latent time of stimuli traveling to the impaired side
- left brain-left leg (lt-lt) indicates the latent time of stimuli traveling to the same side of the brain, namely the healthy side.
- a shorter latent time indicates rapid recovery.
- latent time was shorter than in the PBS or non-Muse cell group for both right brain-left leg (rt-lt) and left brain-left leg (lt-lt), and although statistically significant differences were not observed, the measured values suggested recovery of the neural network.
- the cell preparation of the present invention is able to regenerate brain cells (such as nerve cells or glial cells) at the site of a cerebral infarction by being administered into the cerebral parenchyma of a cerebral infarction model, is able to reduce infarct size and improve brain function, and can be applied to the treatment of cerebral infarction and to the prevention and/or treatment of sequelae following cerebral infarction.
- brain cells such as nerve cells or glial cells
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| US17/219,430 US20210213068A1 (en) | 2014-02-25 | 2021-03-31 | Pluripotent stem cell for treatment of cerebral infarction |
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| JP2014035725A JP6519038B2 (ja) | 2014-02-26 | 2014-02-26 | 脳梗塞治療のための多能性幹細胞 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110772535A (zh) * | 2018-07-12 | 2020-02-11 | 南通大学 | 多系分化持续应激细胞在制备镇痛药物中的应用 |
| CN110869034A (zh) * | 2017-06-20 | 2020-03-06 | 国立大学法人名古屋大学 | 利用多能干细胞进行的伴随胎儿生长迟缓的脑损伤的改善和治疗 |
| US10641762B2 (en) | 2016-01-15 | 2020-05-05 | University Of Toyama | Mobilization of pluripotent stem cells for ischemic cerebral infarction |
| WO2021073041A1 (zh) * | 2019-10-15 | 2021-04-22 | 南通大学 | 多系分化持续应激细胞的应用、治疗周围神经损伤药物及其制备方法 |
| US11419899B2 (en) | 2016-07-29 | 2022-08-23 | Tohoku University | Method of treating aortic aneurysm using muse cells |
| AU2017305067B2 (en) * | 2016-08-03 | 2022-11-03 | Hiroshi Yabuki | Alleviation and treatment of ischemia reperfusion-induced lung injury using pluripotent stem cells |
| US20220395536A1 (en) * | 2019-08-09 | 2022-12-15 | Tohoku University | Agent for treating or preventing vascular dementia |
| US12083149B2 (en) | 2016-08-03 | 2024-09-10 | Tohoku University | Amelioration and treatment of chronic lung disease using pluripotent stem cells |
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| JP6391364B2 (ja) * | 2014-08-25 | 2018-09-19 | 国立大学法人 鹿児島大学 | 認知機能障害改善用細胞製剤 |
| JP6994200B2 (ja) * | 2016-05-16 | 2022-02-04 | 国立大学法人東海国立大学機構 | 多能性幹細胞による周産期脳障害の改善及び治療 |
| CN109963573B (zh) | 2016-08-30 | 2022-08-30 | 国立大学法人新潟大学 | 细胞制剂和细胞制剂的制造方法 |
| JP6604492B2 (ja) * | 2018-04-09 | 2019-11-13 | 株式会社生命科学インスティテュート | 脳梗塞治療のための多能性幹細胞 |
| WO2021140773A1 (ja) * | 2020-01-08 | 2021-07-15 | 公益財団法人神戸医療産業都市推進機構 | 身体機能回復促進剤 |
| JPWO2021201286A1 (enrdf_load_stackoverflow) | 2020-04-02 | 2021-10-07 |
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| US20110070647A1 (en) * | 2009-07-15 | 2011-03-24 | Mari Dezawa | Pluripotent stem cell that can be isolated from body tissue |
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| US20060210544A1 (en) * | 2003-06-27 | 2006-09-21 | Renomedix Institute, Inc. | Internally administered therapeutic agents for cranial nerve diseases comprising mesenchymal cells as an active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110070647A1 (en) * | 2009-07-15 | 2011-03-24 | Mari Dezawa | Pluripotent stem cell that can be isolated from body tissue |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10641762B2 (en) | 2016-01-15 | 2020-05-05 | University Of Toyama | Mobilization of pluripotent stem cells for ischemic cerebral infarction |
| US11419899B2 (en) | 2016-07-29 | 2022-08-23 | Tohoku University | Method of treating aortic aneurysm using muse cells |
| AU2017303905B2 (en) * | 2016-07-29 | 2022-11-10 | Life Science Institute, Inc. | Prophylactic or therapeutic agent for vascular disorder |
| AU2017305067B2 (en) * | 2016-08-03 | 2022-11-03 | Hiroshi Yabuki | Alleviation and treatment of ischemia reperfusion-induced lung injury using pluripotent stem cells |
| US12083149B2 (en) | 2016-08-03 | 2024-09-10 | Tohoku University | Amelioration and treatment of chronic lung disease using pluripotent stem cells |
| CN110869034A (zh) * | 2017-06-20 | 2020-03-06 | 国立大学法人名古屋大学 | 利用多能干细胞进行的伴随胎儿生长迟缓的脑损伤的改善和治疗 |
| CN110772535A (zh) * | 2018-07-12 | 2020-02-11 | 南通大学 | 多系分化持续应激细胞在制备镇痛药物中的应用 |
| US20220395536A1 (en) * | 2019-08-09 | 2022-12-15 | Tohoku University | Agent for treating or preventing vascular dementia |
| WO2021073041A1 (zh) * | 2019-10-15 | 2021-04-22 | 南通大学 | 多系分化持续应激细胞的应用、治疗周围神经损伤药物及其制备方法 |
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| US10993966B2 (en) | 2021-05-04 |
| JP6519038B2 (ja) | 2019-05-29 |
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| US20210213068A1 (en) | 2021-07-15 |
| US20170128494A1 (en) | 2017-05-11 |
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