WO2019210870A1 - 一种年轻化的修复型成纤维细胞的制备方法及其应用 - Google Patents
一种年轻化的修复型成纤维细胞的制备方法及其应用 Download PDFInfo
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Definitions
- the invention belongs to the technical field of cell biology, and relates to a preparation method and application of a youngened repairable fibroblast - especially to regulate JAK-STAT signaling pathway to regulate cell differentiation, dedifferentiation, transdifferentiation, young Methods for aging, aging, apoptosis, and prolonging the life of the body and the preparation and application of their cell products.
- Stem cells are considered to be the "Holy Grail" of regenerative medicine and anti-aging.
- the stem cells in the body will also age, leading to malignant transformation or degradation of multiple organs including bones, cartilage, heart, muscle, brain, skin, pancreas, liver, kidney, and gastrointestinal tract.
- Abnormal immune system function is also associated with aging. In fact, chronic inflammation of tissues and organs is responsible for its degenerative aging. Older cells usually have DNA damage or mutations, telomere shortening, epigenetic, redox, abnormal energy metabolism, decreased proliferative capacity, and increased dead cells. Older stem cells lose their ability to differentiate into certain lineages and abnormally differentiate into other lineages.
- bone marrow mesenchymal stem cells derived from elderly individuals have an increased ability to form osteochondral cartilage and have an increased ability to develop lipids. Therefore, old bone marrow filled with adipose tissue is often called "yellow bone marrow.”
- neural stem cells in the elderly also reduce differentiation into neurons and more differentiate into astrocytes, which is thought to be associated with decreased cognitive ability in the elderly.
- Stem cells are powerful candidates for the treatment or intervention of aging processes and related diseases due to their availability, expandability, pluripotency, growth factor release and immunomodulatory capacity.
- Mesenchymal stem cells have been widely used in clinical, including graft-versus-host disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury, lupus erythematosus, arthritis and aging.
- umbilical cord mesenchymal stem cells are widely considered.
- long-term/multiple use of “non-autologous” cells is always clinically risky. Autologous transplantation is considered safer, and unfortunately, when people age, their mesenchymal stem cells will age.
- iPS Induced pluripotent stem cells
- iPS are young cells that can be obtained from the elderly and have been considered a good source of cells for treatment.
- the induction efficiency of iPS is low, and the introduction of foreign genes involves genetic variation, which is not conducive to clinical application.
- Recently genetic modification has been used as a method of rejuvenation, but this method still carries the risk of off-target and tumorigenicity.
- the invention aims to provide a method for preparing young-type repaired fibroblasts and application thereof, in particular to regulate JAK-STAT signaling pathway to regulate cell differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging, apoptosis and A method of reversing aging and prolonging the life of the organism.
- the cell products obtained by this method (such as repaired fibroblasts, younger mesenchymal stem cells) can be used to prevent, delay and reverse the process of human aging, repair tissue and organ structure. Or function.
- the repaired fibroblasts obtained according to the patented technology have both the characteristics of skin fibroblasts and the characteristics of mesenchymal stem cells, and are therefore named as regenerative fibroblasts (rFibs), which can also be named.
- the induced and rejuvenated mesenchymal stem cell irMSC
- iMSC induced mesenchymal stem cell
- the technical solution of the present invention is as follows: a method for preparing youngened repairable fibroblasts and use thereof, characterized in that the method is to activate or inhibit the JAK-STAT signaling pathway quantitatively and/or periodically.
- the gene or protein target of the method which is highly expressed or highly expressed, underexpressed or inhibited in the JAK-STAT signaling pathway includes: CXCL2 (gene number/Accession: AY577905.1).
- OS1 (gene number/Accession: NM_005633.3), STAT5B (gene number/Accession: NM_012448.3), JAK1 (gene number/Accession: NM_001321857.1), JAK3 (gene number/Accession: NM_000215.3), SOCS3 ( Gene number / Accession: NM_003955.4), IL6ST (gene number / Accession: NM_001243835.1), STAT1 (gene number / Accession: NM_007315.3), STAT2 (gene number / Accession: NM_198332.1), STAT3 (gene number /Accession: NM_213662.1), STAT4 (gene number / Accession: NM_001243835.1), STAT6 (gene number / Accession: NM_001178081.1), STAT5A (gene number / Accession: NM_001288720.1), IRF9 (gene number
- the cell is an initial target cell that regulates JAK-STAT, and the target cell is derived from a mammal such as a human, a mouse, a monkey, a pig, and the target cells include fibroblasts, epithelial cells, adipocytes, blood.
- the target cells include fibroblasts, epithelial cells, adipocytes, blood.
- the cells obtained by the method described are defined in the patent as cells of interest derived from target cells, including various types of cells that produce different characteristics during the process of regulating JAK-STAT in target cells, including the following At least one of them: differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging, and apoptosis.
- the quantification of activation or inhibition of the JAK-STAT signaling pathway is that at least one of the gene or protein target of the JAK-STAT signaling pathway in the target cell is up-regulated or down-regulated by 1 to 300 times relative to the target cell. Multiple stage.
- the timing of activation or inhibition of the JAK-STAT signaling pathway is at least one of high or low or no expression of a gene or a protein target that regulates the JAK-STAT signaling pathway in a target cell, and the regulation time is 24 hours.
- the timing of activation or inhibition of the JAK-STAT signaling pathway is at least one of high or low or no expression of a gene or a protein target that regulates the JAK-STAT signaling pathway in a target cell, and the regulation time is 24 hours.
- At -220 days at least one of the thus obtained target cells or genes or protein targets that maintain the JAK-STAT signaling pathway for a long time is highly expressed or underexpressed or not expressed or restored to the same expression level as the target cells.
- the method can activate or inhibit the JAK-STAT signaling pathway by modulating at least one of the following pathways or targets: NOD-like receptor signaling pathway, Focal adhesion, cell cycle, tricarboxylic acid cycle, TGF beta signaling pathway, WNT signaling pathway, Notch signaling pathway, P53 signaling pathway, insulin signaling pathway, Calcium (calcium) signaling pathway, Interleukin-19, Interleukin-20, Interleukin-22, Interleukin-24, IL7 HDAC (histone deacetylase), PKC signaling pathway, RAR pathway, adenylate cyclase signaling pathway, HMT (histone methyltransferase), DNMT (DNA methyltransferase) and histone demethylase inhibitors.
- the gene or protein target in the NOD-like receptor signaling pathway is selected from the group consisting of NAIP, IL6, CXCL12, NOD1, TAB3, CARD6, CXCL2, CXCL1, CXCL3, CARD8, CARD9, CASP1, CASP12, CASP4,
- the gene or protein target in the Focal adhesion pathway is selected from the group consisting of TNXB, RAPGEF1, ITGB8, SRC, THBS1, ITGA3, VCL, CAPN2, FLT4, FLT1, ITGA3, ITGB1, ITGB3, ITGB5, ITGB6, ITGB7, ITGA1, ITGA10 , ITGA11, ITGA2, ITGA2B, ITGA5, ITGA6, ITGA7, ITGA8, ITGA9, ITGAV, PDRVG, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, BIRC3, BIRC2, BCL2, DOCK1, FN1, HGF, EGF, EGFR, One or more of IGF1, IGF1R, VEGFA, VEGFB, VEGFC, CTNNB1;
- the gene or protein target for regulating the cell cycle is selected from the group consisting of MAD2L1, BUB1, ORC1, ORC2, ORC3, ORC4, ORC5, ORC6, ATM, ATR, CCNA1, CCNA2, CCNB1, CCNB2, CCNB3, CCND1, CCND2, SMAD2, SMAD3, SMAD4, E2F2, E2F2, E2F4, E2F5, EP300, FZR1, GADD45A, GADD45B, GADD45B, STAG1, STAG2, CDC14A, CDC14B, CDC20, CDC25A, CDC25B, MYC, SMC3, CDC16, YWHAH, YWHAB, YWHAQ, One or several of YWHAE, YWHAG, YWHAZ;
- the gene or protein target for regulating the tricarboxylic acid cycle is selected from the group consisting of IDH3G, IDH3B, MDH2, SDHB, OGDH, MDH1, OGDHL, SUCLG1, SUCLG2, SUCLA2, SDHA, SDHB, SDHC, PDHA1, PDHB, ACLY
- IDH3G IDH3B
- MDH2 MDH2, SDHB, OGDH, MDH1, OGDHL, SUCLG1, SUCLG2, SUCLA2, SDHA, SDHB, SDHC, PDHA1, PDHB, ACLY
- the gene or protein target in the TGF beta signaling pathway is selected from the group consisting of ACVR1C, THBS1, FST, TGFB1, TGFBR1, TGFBR2.TGFBR3, BMP4, RUNX3, RUNX2, CREBBP,
- IFNG IFNG
- HRAS FOS
- FOS TGFB2
- TGFB3 ACVRL1, FOXO3, MTOR
- KRAS CREB1, ATF1, ATF2, ATF4, AKT1, AKT2, AKT3, HNF4A, HNF4G, PIK3R3;
- the gene or protein target in the WNT signaling pathway is selected from the group consisting of PRKCA, WNT7B, PRICKLE1, LRP6, CTNNB1, FZD4, CCND2, PRICK, WNT5A, WNT1, WNT10A, WNT11, WNT9A, WNT9B, WNT3, WNT4B Or several
- the gene or protein target in the Notch signaling pathway is selected from the group consisting of CIR1, KAT2B, MAML2, PSEN2, DVL2, RFNG, SNW1, DLL4, DTX3, DLL3, DLL1, DTX1, DTX2,
- CREBBP CREBBP
- CTBP1 CTBP2, JAG1, JAG2, NOTCH1, NOTCH2, NOTCH3, NOTCH4, PSEN1, PSEN2;
- the gene or protein target in the P53 signaling pathway is selected from one or more of CCNG2, SIAH1, BBC3, TP53AIP1, TP53, SETD7, ATF3, CCNA2, CDK2, CCNG1, CHEK1, PRKCDKAT2B, PRL23, PPP2CA;
- the gene or protein target in the Calcium signaling pathway is selected from the group consisting of RYR1, RYR2, RYR3, ESR1, AR (androgen receptor), KDR (kinase insert domain receptor), VDR (vitamin Dreceptor), ITPR1, ITPR2, ITPR3, PDE1A , one or more of PDE1B, PDE1C, PRKCA, PRKCD, PRKCE, PRKCG;
- the gene or protein target in the insulin signaling pathway is selected from one or more of RAPGEF1, PHKG1, PYGL, TRIP10, INS, INSR, IRS1, PDPK1, PIK3CA, HRAS, GRB2, PTPN1, PTPN11.
- the gene or protein target of the PKC is selected from one or more of PRKCA, PRKCB, PRKDC, PRKCZ, PRKCE, PRKCG, PRKCD, PRKCH, PRKCI, PRKCQ, PRKD1, SLC9A5, MAPK3, MAPK9, MAPK8, MAPK1. ;
- the gene or protein target in the RAR is selected from one or more of RARA, RARS, RARB, RARG, RXRA, RXRG, FAM120B, NCOA1, NCOR2
- the gene or protein target for regulating HDAC is selected from one or more of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11;
- the gene or protein target in the adenylate cyclase signaling pathway is selected from the group consisting of PRKAR1A, ADCY10, ADCYAP1, ADCY1, ADCY2, ADCY6, ADCY3, GNAI1, GNAL, GNAT3, PRKACA, PRKAR2B, PRKACB, PRKAR1B, PRKACG, CDKN1B, PRKAR2A, One or several of NCAM1, CDK N1A;
- the gene or protein target in the HMT is selected from one or more of HNMT, DNMT1, KMT2A, EHMT2, EHMT1, KMT2A, DOT1L, EZH2, SETD7, DNMT3B, DNMT3A, SETDB1, S; ETD2;
- the gene or protein target in the DNMT is selected from one or more of DNMT1, DNMT3B, DNMT3A, CDKN2A, CDKN2B, EHMT2, EHMT1, DNMT3L, CDH1, PARP1, MBD2;
- the gene or protein target in the histone demethylase is selected from the group consisting of KDM1A, KDM4A, KDM5A, KDM5B, KDM2A, KDM5C, KDM4B, KDM4C, KDM5D, KDM4D, KDM1B, HISTIH3A, HIST4H4, HIST2H3C, HAT1, One or more of HIST1H4C, HIST1H4F, HIST1H4J, HIST1H2AE, HIST1H2BB, CLOCK, NOCA1;
- the method employs at least one of the following methods: small molecule compound combinations, cytokine combinations or recombinant protein combinations, gene editing techniques, and transgenic techniques;
- the small molecule compound combination includes one or more of the following compounds:
- Histone deacetylase inhibitors include sodium phenylbutyrate, butyrate, sodium butyrate, VPA, Scriptaid, Apicidin, LBH-589 (Panobinostat), MS-275, SAHA (Vorinostat), Trichostatin (TSA), Psammaplin A, splitomicin, SRT1720 , resveratrol, Sirtinol, APHA, CI-994, Depudecin, FK-228, HC-Toxin, ITF-2357 (Givinostat), Chidamide, RGFP 966, PHOB, BG45, Nexturastat A, TMP269, CAY10603, MGCD-0103, Niltubacin, PXD-101 (Belinostat), Pyroxamide, Tubacin, EX-527, BATCP, Cambinol, MOCPAC, PTACH, MC1568, NCH51 and TC-H106;
- TGF- ⁇ receptor inhibitors 616452, LY2109761, Pirfenidone, Repx (E-616452), SB431542, A77-01, A8301, GW788388, ITD-1, SD208, SB525334, LY364947, ASP3029, D4476 and SB505124;
- PKC inhibitors include Go6983, Go6976 and Bisindolylmaleimide I (GF109203X); WNT/ ⁇ -catenin agonists include MAY-262611, CHIR98014, CHIR99021, LiCl, Li2CO3, TD114-2, AZD2858, AZD1080, BIO, Kenpaullone, TWS119, LY2090314, CBM1078, SB216763 and AR-A014418;
- cAMP agonists include Forskolin, IBMX, Prostaglandin E2 (PGE2), NKH477, 8-pCPT-2'-O-Me-cAMP, GSK256066, Apremilast (CC-10004) Roflumilast, Cilomilast, Rolipram, Milrinone, 8-Bromo-cAMP , Dibutyryl-Camp, Sp-8-Br-cAMPs;
- RAR agonists include TTNPB, Bexarotene, Ch55, Tamibarotene, Retinol, AM580, ATRA, Vitamin A, Vitamin A derivatives and 13-cis RA;
- ROCK inhibitors include Y-27632, Y-27632 2HCl, Thiazovivin, Ripasudil (K-115), Fasudil, GSK429286A, RKI-1447 and PKI-1313;
- JNK inhibitors include SP600125, JNK Inhibitor IX, AS601245, AS602801 and JNK-IN-8;
- DNMT inhibitors include RG108, Thioguanine, 5-Aza-2'-deoxycytidine (Decitabine), SGI-1027, Zebularine and 5-Azacytidine ( AZA);
- HMT inhibitors include EPZ004777, EPZ5676, GSK503, BIX 01294 and SGC 0946;
- Inhibitors of histone demethylase include parnate (tranylcypromine), Tranylcypromine (2-PCPA) HCl SP2509, 4SC-202, ORY-1001 (RG-6016), GSKJ1 and GSK-LSD1 JAK-STAT inhibitors including STAT5 -IN-1,JAK3-IN-1,JAK3-IN-7,WP1066,Homoharringtonine,Pyridone 6,Pyridone 6,Artesunate,ruxolitinib,SH-4- 54,Baricitinib,Ruxolitinib phosphate,AG-490,Baricitinib phosphate,SAR -20347,CYT387 Mesylate,AS1517499,Peficitinib,Ruxolitinib sulfate,NSC 74859,Static,Tofacitinib citrate,Pimozide,Oclacitinib maleate,Ruxolitinib
- PKI-402 (PI3K ⁇ / ⁇ / ⁇ / ⁇ and mTOR inhibitor)
- NSC 74859 (S3I-201) (STAT3inhibitor)
- Fludarabine (Fludara) (STAT-1 inhibitor)
- Sorafenib (Nexavar) (VEGFR, PDGFR, c-Raf and B-Raf inhibitor)
- PLX-4720 (B-RafV600E and c-Raf-1Y340D/Y341D inhibitor)
- the cytokine combination or recombinant protein combination includes PDGFAA, PDGFAB, BMP4, IGF1, bFGF, EGF, VEGF, insulin, Activin A, TGF-beta1, Noggin, BMP-2, Shh, IL-6, CXCL10, CXCL12, CXCL2, HGF, IFN gamma, IL-2, IL-6 R alpha, IL-2Ralpha, TNF-alpha, TNF-beta, TPO, IGF2, IGFBP5, IGFBP6, IGFBP4, IGFBP7, IGFBP9, PDGF-BB, MMP3, GDF11 , TIMP2;
- the gene editing technique includes using the crispr/cas9 gene editing technology and TALEN gene editing technology to up-regulate or knock out a gene or protein target in the JAK-STAT signaling pathway, such as STAT5A;
- the transgenic technique includes overexpression of a lentivirus or retrovirus or inhibition of a gene or protein target in the JAK-STAT signaling pathway, such as STAT5A;
- the signaling pathway in the repaired fibroblasts also undergoes changes such as inhibition of the NOD-like receptor signaling pathway; and/or inhibition of the TGF beta receptor signaling pathway; and/or down-regulation of the insulin signaling pathway; and/or wnt signaling Up-regulation of pathway upregulation and/or notch signaling pathway; and/or at least one of downregulation of p53 signaling pathway;
- the method for preparing the repaired fibroblast is characterized in that the target cell of the repaired fibroblast is a common fibroblast, and the common fibroblast is derived from a mammal (such as a human, a monkey, a mouse). , pig) connective tissue (such as blood, skin, bone marrow, heart).
- a mammal such as a human, a monkey, a mouse
- pig connective tissue such as blood, skin, bone marrow, heart.
- the preparation method comprises the following steps: treating a common fibroblast with a combination of small molecule compounds, and finally preparing a repaired fibroblast;
- the small molecule compound combination comprises a Jak-Stat inhibitor, a WNT/ ⁇ -catenin agonist, a group At least one of a protein deacetylase inhibitor and a cAMP agonist.
- the method for preparing repaired fibroblasts further comprises using a RAR agonist, a DNMT inhibitor, an HMT inhibitor, a histone demethylase inhibitor, ascorbate (ascorbic acid), a JNK inhibitor, a PKC inhibitor, a ROCK inhibitor. And at least one of a TGF- ⁇ inhibitor.
- the preparation method of the repaired fibroblast is a first-stage compound and a second-stage compound which are used in stages and in stages, and the first-stage compound is a WNT/ ⁇ -catenin agonist, a histone deacetylase inhibitor And a cAMP agonist; or the first stage compound is a histone deacetylase inhibitor, a TGF-beta receptor inhibitor, a WNT/ ⁇ -catenin agonist and a cAMP agonist;
- the second stage compound includes a histone deacetylase inhibitor, a TGF- ⁇ inhibitor, a WNT/ ⁇ -catenin agonist, a cAMP agonist, a RAR agonist, an HMT inhibitor, an ascorbate (ascorbic acid), a PKC inhibitor , PKC inhibitors and ROCK inhibitors.
- the preparation method is VPA, 0.05-10 mM; CHIR99021, 1-15 ⁇ M; Repsox, 0.5-10 ⁇ M; Forskolin, 3-50 ⁇ M; Go 6983, 1-20 ⁇ M; Y-27632, 1-25 ⁇ M; AM580 0.02-1 ⁇ M; EPZ004777 0.5 to 15 ⁇ M; Vc, 0.2 mM; TTNPB, 0.2 to 20 ⁇ M; 5-Azacytidine, 1 to 15 ⁇ M; SP600125, at least one of 1 to 50 ⁇ M; or first treating a normal fibroblast using a first-stage compound,
- the first phase compound is VPA, 0.05-10 mM; CHIR99021, 1-15 ⁇ M; Repsox, 0.5-10 ⁇ M; Forskolin, 3-50 ⁇ M treated cells for 2-10 days; after the first phase treatment, the second phase compound treatment is used 4 ⁇ For 20 days, the second stage compound is VPA, 0.05-10 mM; CHIR
- the repaired fibroblasts have a telomere length that is 1.5 to 12 times longer than that of the original normal fibroblasts, and the length is close to that of the juvenile individual, and is prepared from the repaired fibroblasts.
- Other types of cells obtained such as osteoblasts, chondrocytes
- telomeres are elongated and exhibit more functional activity than cells of the same animal.
- the repaired fibroblast prepared by any of the methods of claim 9 to 15, wherein the repaired fibroblast produces a cell product (such as cell secretion, cell lysate),
- a cell product such as cell secretion, cell lysate
- tissue engineering materials to delay or reverse the aging of cells, tissues, organs and organisms.
- the repaired fibroblasts are used in the construction of tissue engineering materials to delay or reverse the aging of cells, tissues, organs and organisms.
- the method for producing superfibroblasts characterized in that the preparation method is a rejuvenation and telomere-extended superfibroblast obtained within 3 to 100 days after knocking out the STAT5 gene by ordinary fibroblasts.
- the preparation method comprises the following steps: preparing the young mesenchymal stem cells by treating the mesenchymal stem cells by small molecule compound combination or gene editing;
- the small molecule compound combination comprises a Jak-Stat inhibitor, WNT/ ⁇ - At least one of a catenin agonist, a DNMT inhibitor, a TGF- ⁇ inhibitor, and a cAMP agonist;
- the gene editing treatment method is a gene or protein target (such as STAT5A) that knocks out the Jak-Stat signaling pathway.
- the method for treating the small molecule compound is to treat mesenchymal stem cells for 1 to 28 days, CHIR99021, 1 to 15 ⁇ M; 5-Azacytidine (AZA), 1 ⁇ M to 15 ⁇ M; and/or 5-Azacytidine (AZA) using the following compounds; 1 ⁇ M to 15 ⁇ M; Forskolin, 3 to 50 ⁇ M; and/or 5-Azacytidine (AZA), 1 ⁇ M to 15 ⁇ M; Forskolin, 3 to 50 ⁇ M; CHIR99021, 1 to 15 ⁇ M.
- a cell product (such as a repaired fibroblast) prepared by the method according to any one of claims 1 to 22, or a cell culture solution/base of the cell product, a lysate of a cell product, a kit, a drug, a health product, a food , cosmetics or medical device applications.
- the cell product prepared by any of the methods (such as repaired fibroblasts) is used as a seed cell of tissue engineering materials, a scaffold source of tissue engineering materials, repairing mammalian tissues, organ damage, and repairing tissues and organs degraded by aging. Applications.
- the cell product (such as repaired fibroblasts) prepared by any of the methods described is used in medical research or as an immunomodulator.
- the cell product prepared by any of the methods prevents, delays, and reverses the application of mammalian tissues, organs, and body aging processes in vitro/in vivo.
- the present invention is characterized by regulating cell differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging, apoptosis, reversal of aging and prolonging the body by quantitatively and/or periodically regulating genes or protein targets in the Jak-Stat signaling pathway. life.
- Points include CXCL2, SOS1, STAT5B, JAK1, JAK3, SOCS3, IL6ST, STAT1, STAT2, STAT3, STAT4, STAT6, STAT5A, IRF9, IL6, IL6R, IL2 (eg IL2A and/or IL2B), PRKCD, CXCL12, CXCR4, At least one of JAK2, IL15RA, IL20RB, GHR, and PRLR;
- the small molecule combination for regulating the Jak-Stat signaling pathway includes a Jak-Stat inhibitor, a WNT/ ⁇ -catenin agonist, and histone deacetylation Base enzyme inhibitors and cAMP agonists, RAR agonists, DNMT inhibitors, HMT inhibitors
- the cytokine combination or recombinant protein combination includes PDGFAA, PDGFAB, BMP4, IGF1, bFGF, EGF, VEGF, insulin, Activin A, TGF-beta1, Noggin, BMP-2, Shh, IL-6, CXCL10, CXCL12, CXCL2, HGF, IFN gamma, IL-2, IL-6 R alpha, IL-2Ralpha, TNF-alpha, TNF-beta, TPO, IGF2, IGFBP5, IGFBP6, IGFBP4, IGFBP7, IGFBP9, PDGF-BB, MMP3, GDF11 , TIMP2.
- the gene editing techniques include the use of crispr/cas9 gene editing technology and TALEN gene editing technology to up-regulate or knock out genes or protein targets in the JAK-STAT signaling pathway, such as STAT5A.
- Such transgenic techniques include overexpression of a lentivirus or retrovirus or inhibition of a gene or protein target in the JAK-STAT signaling pathway, such as STAT5A.
- the present invention prepares repaired skin fibroblasts by inhibiting a gene or protein target of a Jak-Stat signaling pathway in fibroblasts (such as STAT5A, JAK1) by a small molecule compound, Jak- in the repaired skin fibroblast.
- a gene or protein target of a Jak-Stat signaling pathway in fibroblasts such as STAT5A, JAK1
- the Stat signaling pathway is inhibited, and the signaling pathway in repaired fibroblasts is also altered by the inhibition of the NOD-like receptor signaling pathway; and/or the TGF beta receptor signaling pathway is inhibited; and/or the insulin signaling pathway is downregulated; and / Or at least one of up-regulation of the wnt signaling pathway and/or downregulation of the notch signaling pathway; and/or down-regulation of the p53 signaling pathway; the telomere length of the repaired dermal fibroblast is prolonged compared to the original normal fibroblast 1.5 to 12 times, the length is close to the level of the same type of cells in the juvenile; other types of cells (such as osteoblasts, chondrocytes) prepared from the repaired fibroblasts, and the same type of cells from the same animal individual In contrast, telomeres are elongated and exhibit greater functional activity; the repaired fibroblasts and the finely prepared cells Cellular products (such as cell secretions, cell lysates) can be used to construct tissue engineering materials
- the present invention provides quantitative and/or timed regulation of genes or protein targets in the Jak-Stat signaling pathway to regulate cell differentiation, dedifferentiation, transdifferentiation, rejuvenation, aging, apoptosis, and reversal of aging and prolonging the lifespan of the body.
- Technology which promotes transdifferentiation between different types of cells, can be used to prepare different types of young cells (such as reversing the senescence of mesenchymal stem cells, preparing superfibroblasts), and can also be used to promote cell senescence and apoptosis.
- the cells prepared by the technology and the products of the cells are used for preventing, delaying, and reversing the aging process of tissues, organs, and organisms of mammals in vitro/in vivo; for programming in cells, tissues, organs, and body weight; Seed cells of tissue engineering materials, scaffold sources of tissue engineering materials, repair of mammalian tissues, organ damage, and repair of tissues and organs degraded by aging.
- Mechanism of the invention By quantitatively and/or timingly regulating the expression of genes or protein targets of the Jak-Stat signaling pathway in cells, changing the changes of different metabolic pathways of cells, thereby changing the cell state of target cells to different types. Other cells have different cellular characteristics.
- the present invention has the following beneficial effects: the repaired fibroblasts provided by the present invention are compared with fibroblasts of the same donor origin or with donor-derived fibroblasts of the same age.
- the repaired fibroblasts are characterized by rejuvenation but are not tumorigenic, such as epigenetic changes and/or changes in the expression levels of senescence-related genes and/or cell telomeres.
- Prolonged and/or increased rate of cell proliferation and/or the ability of cells to have long-term stable passage, and the younger cells and their cellular products can reverse the aging of the mammalian body and prolong life; the quantitation and/or provided by the present invention Systematic regulation of cell differentiation by regularly regulating genes or protein targets in the Jak-Stat signaling pathway to regulate cell differentiation, dedifferentiation, transdifferentiation, rejuvenation, senescence, apoptosis, and reversal of aging and prolonging the lifespan of the organism , dedifferentiation, transdifferentiation, rejuvenation, aging, apoptosis, and the corresponding prepared cells and cell products for prevention, delay, and reversal in vitro/in vivo
- rFib cells have the ability to immunomodulate in vivo.
- rFib has an age-restricted bone defect repair capability.
- Figure 8 Inhibition of the STAT5 gene can rejuvenate skin fibroblasts and gain multi-directional differentiation.
- rFib cells are distributed in multiple organs of mice and can differentiate into functional cells.
- rFib medium can significantly promote skin healing.
- the rFib broth group almost completely healed 12 days after modeling.
- Figure 17 Mix Y treatment inhibits STAT5, STAT3 gene expression (A-B), CDKN1A gene down-regulation, telomere elongation (C-D), and cell rejuvenation.
- FIG. 1 Mix Pn treatment downregulates STAT5 expression (A), ATF3, CDKN1A, GADD45B and IL6 expression (B-E) expression is inhibited, indicating cell rejuvenation.
- Figure 19 Mix Y-Mix Pn2 treatment inhibits fibroblast JAK1 expression (A) and prolongs its telomere length (B).
- FIG. 20 Tuj1 staining of neural cells transformed from skin fibroblasts into cells, A. characterization of B. Nestin expression levels.
- Figure 21 Upregulation of STAT5 gene expression during ES differentiation into nerves using small molecule compounds.
- Figure 22 Module for KEGG pathway enrichment.
- Human skin fibroblasts are seeded into 6-well plates and cultured in skin fibroblast culture medium for 24 hours;
- HG-DMEM supplemented with 10% FBS, 10 ng/mL bFGF, 100 ng/mL PDGF-AB and 10 ng/mL BMP4.
- rFib was cultured in MSC basal medium and passaged when the cell confluence reached 90%.
- Skin fibroblast culture medium 10% FBS + HG-DMEM; or Fibstar-CO medium under the brand name HCell, FMS003C.
- HG-DMEM supplemented with 10% FBS, containing VPA, 0.5 mM; CHIR99021, 3 ⁇ M; Repsox, 1 ⁇ M; Forskolin, 10 ⁇ M; SP600125, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777 5 ⁇ M; Vc, 0.2 mM; TTNPB, 5 ⁇ M.
- VPA 0.5 mM; CHIR99021, 3 ⁇ M; Repx, 1 ⁇ M; Forskolin, 10 ⁇ M; SP600125, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777 5 ⁇ M; Vc, 0.2mM; TTNPB, 5 ⁇ M.
- MSC basal medium 10% FBS + LG-DMEM or bone marrow mesenchymal stem cell complete medium purchased from Cyagen, stock number HUXMA-90011 or rFib medium under the brand name HCRM0016-01.
- Fib skin fibroblasts
- rFib skin fibroblasts
- C Histochemical analysis of cell triline differentiation ability before and after conversion (parental skin cells were derived from P8 generation cells of a 39 year old volunteer). The samples were tested for differentiation on day 0 (Fib, before treatment), day 5, day 12, day 15 (rFib) and after several expansions to determine their osteogenic, adipogenic, and cartilage-forming ability at 21 days.
- Rear Osteoblast (identification of osteogenesis, Alizarin Red staining), Adipocyte (adipogenic, identified by Oil Red staining), Chondrocyte (carcinogenesis, Alician blue staining), and after multiple passages (P9, P16), rFib cells remain Maintained a good three-line differentiation ability.
- JAK1, STAT5 expression changes reduced after treatment
- telomerase (TERT) expression high expression after 5 days
- rFib is safe and not Tumorous cells.
- E-G q-RT-PCR detection of several cellular senescence markers (CDKN1A, ATF3 and IL-6).
- CDKN1A cellular senescence markers
- ATF3 cellular senescence markers
- IL-6 cellular senescence markers
- F-G.q-RT-PCR was used to detect the expression of COL2A1 and MMP13 in bMSCs and rFibs of different ages, and the results were consistent with the staining results.
- rFib teratoma formation test human embryonic stem cells (hESC) as a positive control.
- hESC human embryonic stem cells
- Subcutaneous transplantation of hESC into NOD/SCID mice produced teratomas (with obvious three-layer structure), and no tumors were found in mice transplanted with rFib.
- telomere length and telomerase expression J. Analysis of telomere length and telomerase expression. rFib cells were significantly longer than their homologous Fib cells, and remained stable after induction. However, telomerase was only transiently expressed during induction, and then returned to low expression levels. Different cells (continuous high expression of telomerase in tumor cells) indicate that rFib is younger and not tumorigenic.
- Mitomycin C was treated for 2.5 hours, digested, and cells were seeded at 24 x plate in 1 x 105 cells/well. Lymphocytes were stained with carboxyfluorescein succinimidyl ester (CFDA-SE) for 30 minutes at 37 ° C and seeded in 24-well plates at a density of 2 x 10 5 . Proliferation of lymphocytes was stimulated with PHA at a final concentration of 2 ⁇ g/ml. Five groups were set up: bMSC+lymphocyte+PHA co-culture group, rFib+ lymphocyte+PHA co-culture group, skin fibroblast+lymphocyte+PHA co-culture group, lymphocyte+PHA positive control group, lymphocyte separate negative control group. After 5 days of co-cultivation, lymphocytes in each well were collected and washed three times with PBS. Lymphocyte proliferation was measured by flow cytometry using anti-CD3, CD4 and CD8 antibodies. The antibodies were all from BD biosciences.
- rFib and bMSC were cultured with T cells in a mixed lymphocyte reaction method, respectively.
- B-C.rFib has an ability to regulate CD4+ immune cell subtypes.
- D-E.rFib has an ability to regulate CD8+ immune cell subtypes.
- BMSCs, rFib, and skin fibroblasts cultured for 48 h at a density of 1 ⁇ 10 6 were filtered through a 0.22 ⁇ m filter (Millipore) to remove cells or cell debris, and concentrated 100-fold using an ultrafiltration centrifuge tube.
- mice C57BL/6 mice aged 8 to 12 weeks were injected with concanavalin in PBS at 25 mg/kg body weight to induce acute liver injury and only PBS was injected as a control (Han et al., 2014). 6 mice per group. After 30 minutes, different concentrated media or PBS was injected through the tail vein. After 8.5 hours of tail vein injection of the medium, the mice were sacrificed. Collect blood and liver. The liver was stained with HE, the CD3+ T cells were detected by flow cytometry, and the blood was tested for ALT/AST.
- mice treated with C-D.rFib culture were close to normal levels, and there were no obvious symptoms of liver injury.
- RNA extraction was performed according to the instructions of the TRIzol kit (Takara Bio).
- RNA 1.0 ⁇ g was reverse transcribed into cDNA using Primescript RT kit (Takara Bio).
- Primescript RT kit Takara Bio
- cDNA was used as a template with specific primers and SYBR Green using SYBR Premix EX TaqTMII (Takara Bio). The cycle conditions are as described by the manufacturer (Takara). Relative expression levels were normalized using internal parameters (ACTIN).
- ACTIN internal parameters
- genomic DNA was used as a template for the human-specific primer ACTIN using Premix Taq (Takara Bio).
- Example 2 rFib cells have bone defect repair ability
- a femoral defect model of NOD/SCID mice with a body weight of 20 to 24 g at 8 to 10 weeks of age was used with the approval of the ethics committee. Five animals were used in each group.
- the modeling method was as follows: under the anesthesia of sodium pentobarbital, cut Open the skin and subcutaneous tissue, and bluntly separate between the rectus femoris and the semitendinosus to expose enough midshaft of the femur. Surgery was performed at the infarction of the right femur center. A 4 mm x 1 mm continuous bone defect was surgically constructed.
- mice Twenty-eight days after transplantation, the mice were sacrificed by injection of a lethal dose of sodium pentobarbital. Mice were bluntly isolated, fixed with 4% PFA, detected using ⁇ CT imaging (SkyScan 1272, Bruker microCT), and the collected data were analyzed.
- ⁇ CT imaging SkyScan 1272, Bruker microCT
- A Schematic diagram of the surgical operation of the mouse mid-segment defect model.
- C.rFib cells are labeled with Hoechst 33342 and are autofluorescent blue.
- the repaired section shows that rFib cells form new bone in the defect site, and the number and position correspond to the new bone cells one by one.
- Example 3 rFib cells have cartilage defect repair ability
- NOD/SCID mice weighing 8 to 24 g at 8 to 10 weeks of age were used.
- a modified articular cartilage model was used to evaluate the efficacy of rFib (Cheng et al., 2014).
- Articular cartilage defects (1.5 mm x 1 mm) were constructed in a trochlear groove at the distal end of the femur by a biopsy punch.
- Cells ((2.5 ⁇ 10 5 th use in Matrigel in 35 l) Hoechst 33342 labeled defect site and the implant. The Matrigel implanted without cells as a control.
- A-B Cartilage tissue samples and 10 ⁇ m sections of reddish green staining. In reddish green staining, red is cartilage and green is bone tissue. Young rFib (39 years old) and bMSC (31 years old) can repair cartilage defects. Older bMSC (62 years old), although capable of generating new tissue, has no new cartilage, while older individual-derived rFib (62 years old) remains Cartilage tissue can be formed.
- Panel D the section shows that Hoechst 33342 labeled rFib formed a new cartilage tissue.
- the newly formed cartilage tissue is similar in structure to normal cartilage, and no abnormal tissue is produced.
- Example 4 different types of small molecule compounds were used in combination for different time to obtain repaired fibroblasts, and the identification method was the same as in Example 1, and the combination is shown in the following table (Table 1).
- the gene carried by the lentivirus begins to be expressed after the next day, and the cells can continue to be cultured to further accumulate the expression product or change the cell phenotype.
- the virus-transfected cells were purified using antibiotics, and the cells were further expanded and cultured using HG-DMEM containing 10% FBS; the cells were continuously cultured for 150 days.
- the 12,036 genes identified by WGCNA screened two representative modules of the KEGG pathway enrichment of rFib and a box diagram of the expression changes of two gene modules in several samples of the induction process.
- the STAT5 gene was knocked out and cultured for 40 days. Immunohistochemical staining showed that Fib knockdown STAT5 (Fib-STAT5-KO) H4K20me3 (the aging marker, the more aging) was significantly reduced compared to the control.
- Fib after STAT5 knockout showed osteogenesis (Alizarin Red S, alizarin red staining) and cartilage (Alcian Blue, Alcian blue staining) ability.
- H Schematic diagram of the regulation of the Jak-Stat signaling pathway in fibroblasts to rejuvenate cells and organisms.
- STAT5A is no longer expressed after A. Fib knocks out STAT5.
- the cells were further cultured in a low glucose-DMEM medium of 10% FBS for 3 days, after which ⁇ -galactosidase staining was performed.
- Example 15 intravenous rFib prolongs the lifespan of aging mice
- mice injected with rFib cells can effectively prolong the lifespan of mice regardless of whether the cells are derived from young individuals (39 years old) or elderly individuals (62 years old), even young Fib cells are not prolonged.
- the role of life span, the survival curve and the solvent group were not significantly different.
- mice had marked aging (hair dullness, hunchback), and the mice were significantly improved after 4 weeks of injection of rFib cells, and the mice injected with DMEM were more senescent after 4 weeks;
- GDF11 a protein with anti-aging function
- PDGFA protein for bone formation
- rFib cells are distributed in multiple organs of mice and can differentiate into functional cells.
- A-B.rFib cells are distributed in the stomach, spleen, lung and liver of mice (fluorescence and PCR)
- rFib cells were distributed in the bones of mice (PCR method, 1# ⁇ 10# indicates mouse number, 1# ⁇ 5# is a mouse injected with rFib cells, and 6# ⁇ 10# is injected with DMEM. Mouse)
- Example 16 intravenous rFib increased bone density in aged osteoporotic animals.
- Interventions were performed on senile osteoporosis (28 W NOD/SCID mice) using human cells.
- the experimental group was injected with 1*106rFib cells in 200 ⁇ L DMEM, and the control group was injected with DMEM once a week for 3 weeks.
- the bone marrow density was measured after 28 days from the first injection.
- Micro-CT results showed that the third lumbar vertebrae trabecular structure of the experimental group was more dense.
- BMD bone mineral density
- BV/TV relative bone volume
- Tb.N trabecular bone number
- Example 17 the culture medium of rFib cells can promote wound healing of animal skin
- mice were used to create a 8 cm wide cortical defect on the back, the Control group was not treated, and the rFib Medium group was treated with rFib medium daily.
- rFib medium can significantly promote skin healing.
- the rFib broth group almost completely healed 12 days after modeling.
- Example 18 rFib improves ischemia in the lower limbs of mice
- the lower limb ischemia model was prepared by ligation of the unilateral femoral artery of NOD/SCID mice. After successful laser Doppler verification model, the cells were injected 1 ⁇ 10 6 at the femoral artery ligation point and at the distal and proximal ends. Blood flow was measured using laser Doppler 7 days and 14 days after injection of cells.
- Skin fibroblasts are seeded into 6-well plates and cultured in skin fibroblast culture medium for 24 hours;
- the culture solution was changed to HG-DMEM supplemented with 10% FBS, and the cells were further cultured for 3 days to start the identification; or cultured using rFib medium.
- rFib was cultured in MSC basal medium and passaged when the cell confluence reached 90%.
- Skin fibroblast culture medium 10% FBS + HG-DMEM; or Fibstar-CO medium under the brand name HCell, FMS003C.
- Y-27632, 5 ⁇ M; Vc, 0.2 mM; EPZ004777, 5 ⁇ M; Forskolin, 10 ⁇ M; Repsox, 1 ⁇ M were added to FibGro medium branded as HCell, product number FGS0040.
- MSC basal medium 10% FBS + LG-DMEM or bone marrow mesenchymal stem cell complete medium purchased from Cyagen, stock number HUXMA-90011 or rFib medium under the brand name HCRM0016-01.
- Figure 17 Mix Y treatment inhibits STAT5, STAT3 gene expression (A-B), CDKN1A gene down-regulation, telomere elongation (C-D), and cell rejuvenation.
- Example 20 preparation of rFib cells by combination of different compounds
- Skin fibroblasts are seeded into 6-well plates and cultured in skin fibroblast culture medium for 24 hours;
- the culture solution was changed to HG-DMEM supplemented with 10% FBS, and the cells were further cultured for 3 days to start the identification; or cultured using rFib medium.
- rFib was cultured in MSC basal medium and passaged when the cell confluence reached 90%.
- Skin fibroblast culture medium 10% FBS + HG-DMEM; or Fibstar-CO medium under the brand name HCell, FMS003C.
- HG-DMEM supplemented with 10% FBS, containing VPA, 0.5 mM; CHIR99021, 3 ⁇ M; Repsox, 1 ⁇ M; Forskolin, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777, 5 ⁇ M; Vc , 0.2 mM; TTNPB, 5 ⁇ M; .5-Aza-2'-deoxycytidine, 10 ⁇ M.
- VPA 0.5 mM; CHIR99021, 3 ⁇ M; Repsox, 1 ⁇ M; Forskolin, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777, 5 ⁇ M; Vc, 0.2 mM; TTNPB, 5 ⁇ M; .5-Aza-2'-deoxycytidine, 10 ⁇ M.
- MSC basal medium 10% FBS + LG-DMEM or bone marrow mesenchymal stem cell complete medium purchased from Cyagen, stock number HUXMA-90011 or rFib medium under the brand name HCRM0016-01.
- FIG. 1 Mix Pn treatment downregulates STAT5 expression (A), ATF3, CDKN1A, GADD45B and IL6 expression (B-E) expression is inhibited, indicating cell rejuvenation.
- Skin fibroblasts are seeded into 6-well plates and cultured in skin fibroblast culture medium for 24 hours;
- the rFib-inducing culture solution containing the small molecule compound combination Mix Pn2 is added, and the solution is changed once every 2 days;
- the culture medium was changed to HG-DMEM supplemented with 10% FBS, 10 ng/ml bFGF, 100 ng/ml PDGF-AB and 10 ng/ml BMP4.
- the cells were treated for 3 days; or treated with HG-DMEM supplemented with 10% FBS for 3 days; or cultured with rFib medium; identification was started 3 days later.
- rFib was cultured in MSC basal medium and passaged when the cell confluence reached 90%.
- Skin fibroblast culture medium 10% FBS + HG-DMEM; or Fibstar-CO medium under the brand name HCell, FMS003C.
- Y-27632, 5 ⁇ M; Vc, 0.2 mM; EPZ004777, 5 ⁇ M; Forskolin, 10 ⁇ M; Repsox, 1 ⁇ M were added to FibGro medium branded as HCell, product number FGS0040.
- HG-DMEM supplemented with 10% FBS, containing VPA, 0.5 mM; CHIR99021, 3 ⁇ M; Repsox, 1 ⁇ M; Forskolin, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777, 5 ⁇ M; Vc , 0.2 mM; TTNPB, 5 ⁇ M.
- VPA 0.5 mM; CHIR99021, 3 ⁇ M; Repsox, 1 ⁇ M; Forskolin, 10 ⁇ M; Go 6983, 5 ⁇ M; Y-27632, 5 ⁇ M; AM580 0.05 ⁇ M; EPZ004777, 5 ⁇ M; Vc, 0.2 mM; TTNPB, 5 ⁇ M.
- MSC basal medium 10% FBS + LG-DMEM or bone marrow mesenchymal stem cell complete medium purchased from Cyagen, stock number HUXMA-90011 or rFib medium under the brand name HCRM0016-01.
- Figure 19 Mix Y-Mix Pn2 treatment inhibits fibroblast JAK1 expression (A) and prolongs its telomere length (B)
- Example 22 transdifferentiation of skin fibroblasts into neural cells
- Skin fibroblasts are seeded into 6-well plates and cultured in skin fibroblast culture medium for 24 hours;
- Skin fibroblast culture medium 10% FBS + HG-DMEM; or Fibstar-CO medium under the brand name HCell, FMS003C.
- HG-DMEM supplemented with 10% FBS, containing A8301, 0.5 ⁇ M; bFGF, 10 ng/mL; EPZ004777, 5 ⁇ M; RG 108, 10 ⁇ M; parnate, 2 ⁇ M; CHIR99021, 10 ⁇ M; Forskolin, 50 ⁇ M; VPA, 0.5 mM; 0.05 ⁇ M; BIX 01294, 1 ⁇ M.
- Nerve cell culture medium DMEM/F12, 5 mL; Neurobasal, 5 mL; N2, 1/100; B27, 1/50; cAMP, 100 ⁇ M; BDNF, 20 ng/mL; GDNF, 20 ng/Ml; KOSR, 10% (v/ v).
- the nerve-inducing fluid is replaced by a nerve cell culture solution
- Nerve-inducing fluid DMEM/F12supplemented with 10% KOSR, including bFGF, 10 ng/mL; Y-27632, 5 ⁇ M; VPA, 0.5 mM; EPZ004777, 5 ⁇ M; Forskolin, 10 ⁇ M; Repsox, 1 ⁇ M.
- Nerve cell culture medium DMEM/F12, 5 mL; Neurobasal, 5 mL; N2, 1/100; B27, 1/50; cAMP, 100 ⁇ M; BDNF, 20 ng/mL; GDNF, 20 ng/Ml; KOSR, 10% (v/ v).
- Figure 21 Upregulation of STAT5 gene expression during ES differentiation into nerves using small molecule compounds.
- Example 24 Characteristics of Signal Pathways in rFib Cells Prepared as in Example 1
- rFib cells derived from different individuals were subjected to transcriptome sequencing, and 12036 genes of each cell sample were analyzed by WGCNA to obtain 12 clustering modules.
- the bar graph shows 12 modules enriched by the KEGG pathway, and the representative genes of each KEGG pathway are displayed in the order of the gene members.
- the box plot shows the distribution of average gene expression levels in each module.
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Abstract
Description
Claims (10)
- 一种年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞中的Jak-Stat信号通路被抑制;所述Jak-Stat信号通路中低表达或被抑制表达的基因或蛋白质靶点包括CXCL2(基因号/Accession:AY577905.1),SOS1(基因号/Accession:NM_005633.3)、STAT5B(基因号/Accession:NM_012448.3)、JAK1(基因号/Accession:NM_001321857.1)、JAK3(基因号/Accession:NM_000215.3)、SOCS3(基因号/Accession:NM_003955.4)、IL6ST(基因号/Accession:NM_001243835.1)、STAT1(基因号/Accession:NM_007315.3)、STAT2(基因号/Accession:NM_198332.1)、STAT3(基因号/Accession:NM_213662.1)、STAT4(基因号/Accession:NM_001243835.1)、STAT6(基因号/Accession:NM_001178081.1)、STAT5A(基因号/Accession:NM_001288720.1)、IRF9(基因号/Accession:NM_006084.4)、IL6(基因号/Accession:XM_005249745.5)、IL6R(基因号/Accession:NM_181359.2)、IL2(基因号/Accession:NM_000586.3)(如IL2A和/或IL2B)、PRKCD(基因号/Accession:NM_001354679.1)、CXCL12(基因号/Accession:NM_000609.6)、CXCR4(基因号/Accession:NM_003467.2)、JAK2(基因号/Accession:NM_004972.3)、IL15RA(基因号/Accession:NM_001351095.1)、IL20RB(基因号/Accession:XM_006713665.4)、GHR(基因号/Accession:NM_001242406.2)和PRLR(基因号/Accession:NM_001204314.2)中的至少一种。
- 如权利要求1所述的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述修复型成纤维细胞中的信号通路还发生了如下变化:NOD-like receptor信号通路受到抑制;和/或TGF beta信号通路受到抑制;和/或insulin信号通路下调;和/或wnt信号通路上调和/或notch信号通路下调;和/或p53信号通路下调;和/或上调RAR通路;和/或PKC信号通路下调;和/或抑制HDAC((组蛋白脱乙酰基酶);和/或激动adenylate cyclase;和/或抑制HMT(组蛋白甲基转移酶)信号通路中的至少一种;所述的NOD-like receptor信号通路中的基因或蛋白质靶点选自NAIP,IL6,CXCL12,NOD1,TAB3,CARD6,CXCL2,CXCL1,CXCL3,CARD8,CARD9,CASP1,CASP12,CASP4,CASP5,NFKB1,TMEM173,TNF,NFKBIB,NOD2,PYDC1,PYCARD,TAB1,TAB2,TNF,TLR4,NLRP1,NLRP12,NLRP3,NLRP6,MCU,RIPK3,RHOA,TAK1,BIRC2,ATG16L1,ATG5,ATG12,TANK中的一种或几种;所述的TGF beta信号通路中的基因或蛋白质靶点选自ACVR1C,THBS1,FST,TGFB1,TGFBR1,TGFBR2.TGFBR3,BMP4,RUNX3,RUNX2,CREBBP,IFNG,HRAS,FOS,TGFB2,TGFB3,ACVRL1,FOXO3,MTOR,KRAS,CREB1,ATF1,ATF2,ATF4,AKT1,AKT2,AKT3,HNF4A,HNF4G,PIK3R3中的一种或几种;所述的WNT信号通路中的基因或蛋白质靶点选自PRKCA,WNT7B,PRICKLE1,LRP6,CTNNB1,FZD4,CCND2,PRICK,WNT5A,WNT1,WNT10A,WNT11,WNT9A,WNT9B,WNT3,WNT4B中的一种或几种;所述的Notch信号通路中的基因或蛋白质靶点选自CIR1,KAT2B,MAML2,PSEN2,DVL2,RFNG,SNW1,DLL4,DTX3,DLL3,DLL1,DTX1,DTX2,CREBBP,CTBP1,CTBP2,JAG1,JAG2,NOTCH1,NOTCH2,NOTCH3,NOTCH4,PSEN1,PSEN2中的一种或几种;所述的P53信号通路中的基因或蛋白质靶点选自CCNG2,SIAH1,BBC3,TP53AIP1,TP53,SETD7,ATF3,CCNA2,CDK2,CCNG1,CHEK1,PRKC DKAT2B,PRL23,PPP2CA中的一种或几种;所述的insulin信号通路中的基因或蛋白质靶点选自RAPGEF1,PHKG1,PYGL,TRIP10,INS,INSR,IRS1,PDPK1,PIK3CA,HRAS,GRB2,PTPN1,PTPN11中的一种或几种;所述的PKC的基因或蛋白质靶点选自PRKCA,PRKCB,PRKDC,PRKCZ,PRKCE,PRKCG,PRKCD,PRKCH,PRKCI,PRKCQ,PRKD1,SLC9A5,MAPK3,MAPK9,MAPK8,MAPK1中的一种或几种;所述的RAR中的基因或蛋白质靶点选自RARA,RARS,RARB,RARG,RXRA,RXRG,FAM120B,NCOA1,NCOR2中的一种或几种;所述的调控HDAC的基因或蛋白质靶点选自HDAC1,HDAC2,HDAC3,HDAC4,HDAC5,HDAC6,HDAC7,HDAC8,HDAC9,HDAC10,HDAC11中的一种或几种;所述的adenylate cyclase信号通路中的基因或蛋白质靶点选自PRKAR1A,ADCY10,ADCYAP1,ADCY1,ADCY2,ADCY6,ADCY3,GNAI1,GNAL,GNAT3,PRKACA,PRKAR2B,PRKACB,PRKAR1B,PRKACG,CDKN1B,PRKAR2A,NCAM1,CDKN1A中的一种或几种;所述的HMT中的基因或蛋白质靶点选自HNMT,DNMT1,KMT2A,EHMT2,EHMT1,KMT2A,DOT1L,EZH2,SETD7,DNMT3B,DNMT3A,SETDB1,SETD2中的一种或几种。
- 如权利要求1或2所述的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞来源于普通成纤维细胞,所述的普通成纤维细胞来源于哺乳动物(如人,猴,鼠,猪)的结缔组织(如血液,皮肤,骨髓,心脏)。
- 如权利要求1~3所述的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞是通过对普通成纤维细胞进行小分子化合物组合的处理,最终制备得到修复型成纤维细胞;所述的小分子化合物组合包括Jak-Stat抑制剂,WNT/β-catenin激动剂,HDAC(组蛋白脱乙酰基酶)抑制剂和adenylate cyclase(cAMP)激动剂中的至少一种。
- 如权利要求1~4所述年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述修复型成纤维细胞的制备方法还包括使用RAR小分子激动剂, DNMT小分子抑制剂,HMT小分子抑制剂,组蛋白去甲基化酶小分子抑制剂,ascorbate(抗坏血酸),JNK小分子抑制剂,PKC小分子抑制剂,ROCK小分子抑制剂,TGF-β小分子抑制剂和细胞因子组合或重组蛋白组合中的至少一种;HDAC(组蛋白脱乙酰基酶)抑制剂包括sodium phenylbutyrate,butyrate,sodium butyrate,VPA,Scriptaid,Apicidin,LBH-589(Panobinostat),MS-275,SAHA(Vorinostat),Trichostatin(TSA),Psammaplin A,splitomicin,SRT1720,resveratrol,Sirtinol,APHA,CI-994,Depudecin,FK-228,HC-Toxin,ITF-2357(Givinostat),Chidamide,RGFP 966,PHOB,BG45,Nexturastat A,TMP269,CAY10603,MGCD-0103,Niltubacin,PXD-101(Belinostat),Pyroxamide,Tubacin,EX-527,BATCP,Cambinol,MOCPAC,PTACH,MC1568,NCH51和TC-H106;TGF-β抑制剂:616452,LY2109761,Pirfenidone,Repsox(E-616452),SB431542,A77-01,A8301,GW788388,ITD-1,SD208,SB525334,LY364947,ASP3029,D4476和SB505124;PKC抑制剂包括Go6983,Go6976和Bisindolylmaleimide I(GF109203X);WNT/β-catenin激动剂包括MAY-262611,CHIR98014,CHIR99021,LiCl,Li2CO3,TD114-2,AZD2858,AZD1080,BIO,Kenpaullone,TWS119,LY2090314,CBM1078,SB216763和AR-A014418;adenylate cyclase(cAMP)激动剂包括Forskolin,IBMX,ProstaglandinE2(PGE2),NKH477,8-pCPT-2′-O-Me-cAMP,GSK256066,Apremilast(CC-10004)Roflumilast,Cilomilast,Rolipram,Milrinone,8-Bromo-cAMP,Dibutyryl-Camp,Sp-8-Br-cAMPs;RAR激动剂包括TTNPB,Bexarotene,Ch55,Tamibarotene,Retinol,AM580,ATRA,Vitamin A、Vitamin A衍生物和13-cis RA;ROCK抑制剂包括Y-27632,Y-27632 2HCl,Thiazovivin,Ripasudil(K-115),Fasudil,GSK429286A,RKI-1447和PKI-1313;JNK抑制剂包括SP600125,JNK Inhibitor IX,AS601245,AS602801和JNK-IN-8;DNMT抑制剂包括RG108,Thioguanine,5-Aza-2'-deoxycytidine(Decitabine),SGI-1027,Zebularine和5-Azacytidine(AZA);HMT抑制剂包括EPZ004777,EPZ5676,GSK503,BIX 01294和SGC 0946;组蛋白去甲基化酶的抑制剂包括parnate(tranylcypromine),Tranylcypromine(2-PCPA)HCl SP2509,4SC-202,ORY-1001(RG-6016),GSKJ1和GSK-LSD1;JAK-STAT抑制剂包括STAT5-IN-1,JAK3-IN-1,JAK3-IN-7,WP1066,Homoharringtonine,Pyridone 6,Pyridone 6,Artesunate,ruxolitinib,SH-4-54,Baricitinib,Ruxolitinib phosphate,AG-490,Baricitinib phosphate,SAR-20347,CYT387 Mesylate,AS1517499,Peficitinib,Ruxolitinib sulfate,NSC 74859,Stattic,Tofacitinib citrate,Pimozide,Oclacitinib maleate,Ruxolitinib S enantiomer,SB1317,Niclosamide,Scutellarin,Solcitinib,Mogrol,Nifuroxazide,TG101348(SAR302503),AG-1478(Tyrphostin AG-1478)(EGFR inhibitor);KX2-391(Src inhibitor);PKI-402(PI3Kα/β/γ/δand mTOR inhibitor);NSC 74859(S3I-201)(STAT3 inhibitor);Fludarabine(Fludara)(STAT-1 inhibitor);U0126-EtOH(UO126 EtOH)(MEK1 and MEK2 inhibitor);SGI-1776 free base(Pim1,Pim2 and Pim3 inhibitor);Sorafenib(Nexavar)(VEGFR,PDGFR,c-Raf and B-Raf inhibitor);PLX-4720(B-RafV600E and c-Raf-1Y340D/Y341D inhibitor);所述的细胞因子组合或重组蛋白组合包括PDGFAA,PDGFAB,BMP4,IGF1,bFGF,EGF,VEGF,insulin,ActivinA,TGF-beta1,Noggin,BMP-2,Shh,IL-6,CXCL10,CXCL12,CXCL2,HGF,IFN gamma,IL-2,IL-6 R alpha,IL-2Ralpha,TNF-alpha,TNF-beta,TPO,IGF2,IGFBP5,IGFBP6,IGFBP4,IGFBP7,IGFBP9,PDGF-BB,MMP3,GDF11,TIMP2。
- 如权利要求1~5所述年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述修复型成纤维细胞的制备方法为按时序分阶段使用的第一阶段化合物和第二阶段化合物,所述第一阶段化合物为WNT/β-catenin激动剂,组蛋白脱乙酰基酶抑制剂和adenylate cyclase(cAMP)激动剂;或所述第一阶段化合物为组蛋白脱乙酰基酶抑制剂,TGF-β抑制剂,WNT/β-catenin激动剂和adenylate cyclase(cAMP)激动剂;所述第二阶段化合物包括组蛋白脱乙酰基酶抑制剂,TGF-β抑制剂,WNT/β-catenin激动剂,adenylate cyclase(cAMP)激动剂,RAR激动剂,HMT抑制剂,ascorbate(抗坏血酸),PKC抑制剂和ROCK抑制剂。
- 根据权利要求1~6所述的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞的制备方法为使用下列化合物处理普通成纤维细胞,使用VPA,0.05~10mM;CHIR99021,1~15μM;Repsox,0.5~10μM;Forskolin,3~50μM;Go 6983,1~20μM;Y-27632,1~25μM;AM5800.02~1μM;EPZ004777 0.5~15μM;Vc,0.2mM;TTNPB,0.2~20μM;5-Azacytidine,1~15μM;SP600125,1~50μM中的至少一种;或者首先使用第一阶段化合物处理普通成纤维细胞,所述的第一阶段化合物为VPA,0.05~10mM;CHIR99021,1~15μM;Repsox,0.5~10μM;Forskolin,3~50μM处理细胞2~10天;第一阶段处理后,使用第二阶段化合物处理细胞4~20天,所述的第二阶段化合物为VPA,0.05~10mM;CHIR99021,1~15μM;Repsox,0.5~10μM;Forskolin,3~50μM;Go 6983,1~20μM;Y-27632,1~25μM;AM580 0.02~1μM;EPZ004777 0.5~15μM;Vc,0.2mM;TTNPB,0.2~20μM。
- 如权利要求1~7所述的任一方法制备的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞具备年轻化的特征,其端粒长度与初始的普通成纤维细胞相比,延长了1.5~12倍,长度接近于未成年个体同类细胞的水平;由所述的修复型成纤维细胞制备得到的其它类型细胞(如成骨细胞,软骨细胞),与来自同一动物个体的同类细胞相比,端粒延长,并且表现出更强的功能活性(如成骨活性,成软骨活性)。
- 如权利要求1~8所述的任一方法制备的年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,所述的修复型成纤维细胞制备的细胞产物(如细胞分泌物,细胞裂解液,修复型成纤维细胞分化的其它类型细胞),在构建组织工程材料,修复哺乳动物组织、器官损伤以及修复衰老退化的组织、器官中的应用,延缓或者逆转细胞、组织、器官和机体衰老中的应用;所述的修复型成纤维细胞,在构建组织工程材料,修复哺乳动物组织、器官损伤以及修复衰老退化的组织、器官中的应用,延缓或者逆转细胞、组织、器官和机体衰老中的应用。
- 根据权利要求1~9所述年轻化的修复型成纤维细胞的制备方法及其应用,其特征在于,任一所述的方法及其制备得到的细胞产品(如修复型成纤维细胞) 或所述细胞产品的衍生物如细胞培养液/基、细胞产品的裂解液、试剂盒、药物、保健品、食品、化妆品或医疗器械的应用;任一所述的方法及其制备得到的细胞产品和/或细胞产品的衍生物作为组织工程材料的种子细胞、组织工程材料的支架来源、修复哺乳动物组织、器官损伤以及修复衰老退化的组织、器官中的应用;任一所述的方法及其制备得到的细胞产品和/或细胞产品的衍生物在医学研究或者作为免疫调节剂中的应用;任一所述的方法及其制备得到的细胞产品和/或细胞产品的衍生物在体外/体内预防、延缓、逆转哺乳动物的组织、器官、机体衰老进程中的应用;任一所述的方法及其制备得到的细胞产品和/或细胞产品的衍生物在细胞、组织、器官、机体重编程或者细胞、组织、器官、机体年轻化中的应用。
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