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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (2) : 152-165     DOI: 10.1007/s11684-016-0445-z
REVIEW |
Chemical transdifferentiation: closer to regenerative medicine
Aining Xu,Lin Cheng()
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Abstract  

Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functional cells. This process is crucial in regenerative medicine. However, the cell-converting strategies, which mainly depend on the virus-mediated expression of exogenous genes, have clinical safety concerns. Small molecules with compelling advantages are a potential alternative in manipulating cell fate conversion. In this review, we briefly retrospect the nature of cell transdifferentiation and summarize the current developments in the research of small molecules in promoting cell conversion. Particularly, we focus on the complete chemical compound-induced cell transdifferentiation, which is closer to the clinical translation in cell therapy. Despite these achievements, the mechanisms underpinning chemical transdifferentiation remain largely unknown. More importantly, identifying drugs that induce resident cell conversion in vivo to repair damaged tissue remains to be the end-goal in current regenerative medicine.

Keywords cell therapy      cell transdifferentiation      chemical compounds      small molecules      tissue regeneration     
Corresponding Authors: Lin Cheng   
Just Accepted Date: 05 April 2016   Online First Date: 29 April 2016    Issue Date: 27 May 2016
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0445-z     OR     http://academic.hep.com.cn/fmd/EN/Y2016/V10/I2/152
In vitro or ?in vivo Species Cell types Chemical compounds References
Starting cells Ending cells
In vitro Mouse Fibroblasts ??Neural ??stem cells Intestinal epithelial ??cells Pluropotent stem cells Repsox, CHIR99021, Forskolin, VPA, DZNep?? & PD0325901 with or w/o BrdU [8689]
In vitro Mouse Human Fibroblasts??Urinal cells Neural progenitor cells Repsox, CHIR99021 & VPA [62]
In vitro Human Fibroblasts Neural progenitor cells 5-Aza [64]
In vitro Mouse Fibroblasts Neural stem cells A-83-01, CHIR99021, VPA, BIX01294, ??RG108, PD0325901 & vitamin C [63]
In vitro Mouse Fibroblasts Neurons SB431542, CHIR99021, Forskolin, ISX9 ??& I-BET151 [67]
In vitro Mouse Fibroblasts Neurons SB431542 & ATRA [68]
In vitro Human Fibroblasts Neurons SB431542, CHIR99021, Forskolin, ??Pifithrin-α, LDN193189 & PD0325901 [66]
In vitro Human Fibroblasts Neurons Repsox, CHIR99021, Forskolin, VPA, ??SP600125, Go 6983 & Y-27632 [65]
In vitro Mouse Astrocytes Neurons Repsox & VPA [69]
In vivo Mouse Glial cells Neurons VPA [72]
In vitro Human Astrocytes Neurons SB431542, CHIR99021, VPA, LDN193189, ??DAPT, Tzv, TTNPB, SAG & Purmo [70]
In vitro Human Fibroblasts Schwann cells SB431542, CP21, VPA & CB [73]
In vitro Mouse Fibroblasts Cardiomyocytes Repsox, CHIR99021, Forskolin, VPA, Parnate ??& TTNPB [75]
In vitro Mouse Fibroblasts Cardiomyocytes A-83-01, CHIR99021, Forskolin, SC1 & (±)-??BayK 8644 [74]
In vitro Human Fibroblasts Insulin-secreting cells 5-Aza [76]
In vitro Human Fibroblasts Insulin-secreting cells Nicotinamide [77]
In vitro Human Fibroblasts Endothelial cells Poly(I:C) [82]
In vitro ?In vivo Mouse Fibroblasts Endothelial cells RITA [81]
In vitro Human Granulosa cells Muscle cells 5-Aza [83]
Tab.1  Cell transdifferentiation and cell reprogramming enabled by complete chemical compounds
Compound Alternative name Function Induced cells Structure
Repsox E616452 Potent and selective inhibitor of TGFbRI Pluripotent stem cells, neural progenitor cells, neurons, cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu1.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu1.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
SB431542 301836-41-9 Potent, selective inhibitor of TGFbRI, ALK4 and ALK7 Neurons, Schwann cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu2.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu2.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
A-83-01 909910-43-6 Selective inhibitor of TGFbRI, ALK4 and ALK7 Neural stem cells, cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu3.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu3.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
LDN193189 1062368-24-4 Highly selective antagonist of BMP receptor isotypes ALK2 and ALK3 Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu4.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu4.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
CHIR99021 CT99021 Highly selective GSK3 inhibitor Pluripotent stem cells, neural progenitor cells, neural stem cells, neurons, cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu5.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu5.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
CP21 CP21R7 GSK3b inhibitor Schwann cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu6.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu6.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Forskolin Colforsin Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP Pluripotent stem cells, neurons, cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu7.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu7.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
VPA Sodium valproate Histone deacetylase inhibitor Pluripotent stem cells, neural progenitor cells, neural stem cells, neurons, cardiomyocytes, Schwann cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu8.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu8.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
5-Aza 5-azacytidine DNA methyltransferase inhibitor Neural progenitor cells, insulin-secreting cells, muscle cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu9.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu9.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
RG108 N-phthalyl-L-tryptophan DNA methyltransferase inhibitor Neural stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu10.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu10.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
BIX01294 935693-62-2 Histone lysine methyltransferase inhibitor Neural stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu11.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu11.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Parnate Tranylcypromine Inhibitor of lysine-specific demethylase and monoamine oxidase, also inhibits histone demethylation Pluripotent stem cells, cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu12.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu12.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
DZNep 3-deazaneplanocin S-adenosylhomocysteine hydrolase inhibitor and histone methyltransferase EZH2 inhibitor Pluripotent stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu13.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu13.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
PD0325901 391210-10-9 Potent MEK1 and MEK2 inhibitor Pluripotent stem cells, neurons, neuron stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu14.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu14.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Y-27632 N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide Selective p160ROCK inhibitor, also inhibits PRK2 Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu15.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu15.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Tzv Thiazovivin Selective ROCK inhibitor Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu16.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu16.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Pifithrin-a PFTa Inhibitor of p53 Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu17.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu17.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
RITA NSC 652287 MDM2-p53 interaction inhibitor Endothelial cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu18.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu18.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
SAG Smoothened agonist Potent Smoothened receptor agonist; activates the Hedgehog signaling pathway Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu19.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu19.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Purmo Purmorphamine Smoothened receptor agonist Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu20.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu20.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Poly(I:C) Polyinosinic-polycytidylic acid Toll-like receptor 3 agonist Endothelial cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu21.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu21.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
SP600125 1,9-pyrazoloanthrone Selective Jun N-terminal kinase inhibitor Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu22.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu22.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
ISX9 N-cyclopropyl-5-(2-thienyl)-3-isoxazolecarboxamide Neurogenic agent Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu23.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu23.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
I-BET151 GSK1210151A BET bromodomain inhibitor Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu24.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu24.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
ATRA Retinoic acid Retinoic acid receptor agonist Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu25.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu25.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Nicotinamide Vitamin B3 Inhibitor of poly(ADP-ribose) polymerase enzymes NAD+ precursor Insulin-secreting cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu26.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu26.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Go 6983 Goe 6983 Broad spectrum protein kinase C inhibitor Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu27.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu27.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
SC1 Pluripotin Dual inhibitor of extracellular signal-regulated kinase 1 and RasGAP Cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu28.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu28.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
(±)-Bay K 8644 71145-03-4 Ca2+ channel activator (L-type) Cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu29.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu29.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
TTNPB Arotinoic acid Analog of retinoic acid Cardiomyocytes <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu30.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu30.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
BrdU 5-bromo-2-deoxyuridine Synthetic thymidine analog Pluripotent stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu31.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu31.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
CB Compound-B Promote proliferation of neural stem cells Schwann cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu32.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu32.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
DAPT g-secretase inhibitor IX g-secretase inhibitor Neurons <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu33.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu33.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Vitamin C L-ascorbic acid Antioxidant Neural stem cells <InlineMediaObject OutputMedium="Online"><ImageObject FileRef="fmd-16211-cl.doc_images\fmd-16211-cl-tu34.jpg" ScaleToFitWidth="10cm" ScaleToFit="1"/></InlineMediaObject><InlineMediaObject OutputMedium="All"><ImageObject FileRef="FMD-16211-CL.doc_images\FMD-16211-CL-tu34.tif" ScaleToFit="1" ScaleToFitWidth="10cm"/></InlineMediaObject>
Tab.2  Chemical compounds reported in chemical transdifferentiation
Fig.1  Chemical transdifferentiation leads to tissue regeneration. Transplantation of chemically induced cells from easily accessible cells by small molecules in vitro may help tissue regeneration after injury, which is closer to clinical translation for cell-based therapy. Administration of drugs identified in in vitro assay may directly convert resident cells around locally damaged sites into desirable cells in vivo and improve functional recovery of injured tissue or organs, which is one of the terminal goals for regenerative medicine.
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