Please wait a minute...
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
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
Download: PDF(729 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

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:     OR
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.
1 Waddington CH. The Strategy of the Genes: a Discussion of Some Aspects of Theoretical Biology. London: Allen & Unwin, 1957
2 Xu J, Du Y, Deng H. Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 2015; 16(2): 119–134
doi: 10.1016/j.stem.2015.01.013 pmid: 25658369
3 Xu Y, Shi Y, Ding S. A chemical approach to stem-cell biology and regenerative medicine. Nature 2008; 453(7193): 338–344
doi: 10.1038/nature07042 pmid: 18480815
4 Tsonis PA, Madhavan M, Tancous EE, Del Rio-Tsonis K. A newt’s eye view of lens regeneration. Int J Dev Biol 2004; 48(8-9): 975–980
doi: 10.1387/ijdb.041867pt pmid: 15558488
5 Tsonis PA, Madhavan M, Call M K, Gainer S, Rice A, Del Rio-Tsonis K. Effects of a CDK inhibitor on lens regeneration. Wound Repair Regen 2004;12:24–29
doi: 10.1111/j.1067-1927.2004.012107.x
6 Hajduskova M, Ahier A, Daniele T, Jarriault S. Cell plasticity in Caenorhabditis elegans: from induced to natural cell reprogramming. Genesis 2012; 50(1): 1–17
doi: 10.1002/dvg.20806 pmid: 21932439
7 Henry JJ, Thomas AG, Hamilton PW, Moore L, Perry KJ. Cell signaling pathways in vertebrate lens regeneration. Curr Top Microbiol Immunol 2013; 367: 75–98
doi: 10.1007/82_2012_289 pmid: 23224710
8 Tsonis PA, Vergara MN, Spence JR, Madhavan M, Kramer EL, Call MK, Santiago WG, Vallance JE, Robbins DJ, Del Rio-Tsonis K. A novel role of the hedgehog pathway in lens regeneration. Dev Biol 2004; 267(2): 450–461
doi: 10.1016/j.ydbio.2003.12.005 pmid: 15013805
9 Maki N, Martinson J, Nishimura O, Tarui H, Meller J, Tsonis PA, Agata K. Expression profiles during dedifferentiation in newt lens regeneration revealed by expressed sequence tags. Mol Vis 2010; 16: 72–78
pmid: 20090923
10 Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51(6): 987–1000
doi: 10.1016/0092-8674(87)90585-X pmid: 3690668
11 Tapscott SJ, Davis RL, Thayer MJ, Cheng PF, Weintraub H, Lassar AB. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 1988; 242(4877): 405–411
doi: 10.1126/science.3175662 pmid: 3175662
12 Kulessa H, Frampton J, Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev 1995; 9(10): 1250–1262
doi: 10.1101/gad.9.10.1250 pmid: 7758949
13 Shen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2000; 2(12): 879–887
doi: 10.1038/35046522 pmid: 11146651
14 Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Götz M. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 2002; 5(4): 308–315
doi: 10.1038/nn828 pmid: 11896398
15 Yamanaka S, Takahashi K.Induction of pluripotent stem cells from mouse fibroblast cultures. Protein, Nucleic acid, Enzyme (Tanpakushitsu Kakusan Koso) 2006; 51: 2346–2351 (in Japanese)
16 Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 2010; 8(5): e1000373
doi: 10.1371/journal.pbio.1000373 pmid: 20502524
17 Karow M, Sánchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascón S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Götz M, Berninger B. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 2012; 11(4): 471–476
doi: 10.1016/j.stem.2012.07.007 pmid: 23040476
18 Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 2009; 460(7259): 1154–1158
doi: 10.1038/nature08262 pmid: 19641492
19 Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K, Hill JA, DiMaio JM, Baker LA, Bassel-Duby R, Olson EN. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci USA 2013; 110(14): 5588–5593
doi: 10.1073/pnas.1301019110 pmid: 23487791
20 Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K, Tohyama S, Yuasa S, Kokaji K, Aeba R, Yozu R, Yamagishi H, Kitamura T, Fukuda K, Ieda M. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci USA 2013; 110(31): 12667–12672
doi: 10.1073/pnas.1304053110 pmid: 23861494
21 Hiramatsu K, Sasagawa S, Outani H, Nakagawa K, Yoshikawa H, Tsumaki N. Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. J Clin Invest 2011; 121(2): 640–657
doi: 10.1172/JCI44605 pmid: 21293062
22 Han JK, Chang SH, Cho HJ, Choi SB, Ahn HS, Lee J, Jeong H, Youn SW, Lee HJ, Kwon YW, Cho HJ, Oh BH, Oettgen P, Park YB, Kim HS. Direct conversion of adult skin fibroblasts to endothelial cells by defined factors. Circulation 2014; 130(14): 1168–1178
doi: 10.1161/CIRCULATIONAHA.113.007727 pmid: 25186941
23 Pereira CF, Chang B, Qiu J, Niu X, Papatsenko D, Hendry CE, Clark NR, Nomura-Kitabayashi A, Kovacic JC, Ma’ayan A, Schaniel C, Lemischka IR, Moore K. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 2013; 13(2): 205–218
doi: 10.1016/j.stem.2013.05.024 pmid: 23770078
24 Batta K, Florkowska M, Kouskoff V, Lacaud G. Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Reports 2014; 9(5): 1871–1884
doi: 10.1016/j.celrep.2014.11.002 pmid: 25466247
25 Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 2010; 468(7323): 521–526
doi: 10.1038/nature09591 pmid: 21057492
26 Feng R, Desbordes SC, Xie H, Tillo ES, Pixley F, Stanley ER, Graf T. PU.1 and C/EBPα/β convert fibroblasts into macrophage-like cells. Proc Natl Acad Sci USA 2008; 105(16): 6057–6062
doi: 10.1073/pnas.0711961105 pmid: 18424555
27 Hendry CE, Vanslambrouck JM, Ineson J, Suhaimi N, Takasato M, Rae F, Little MH. Direct transcriptional reprogramming of adult cells to embryonic nephron progenitors. J Am Soc Nephrol 2013; 24(9): 1424–1434
doi: 10.1681/ASN.2012121143 pmid: 23766537
28 Lemper M, Leuckx G, Heremans Y, German MS, Heimberg H, Bouwens L, Baeyens L. Reprogramming of human pancreatic exocrine cells to b-like cells. Cell Death Differ 2015; 22(7): 1117–1130
doi: 10.1038/cdd.2014.193 pmid: 25476775
29 Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Südhof TC, Wernig M. Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep 2014; 3(2): 282–296
doi: 10.1016/j.stemcr.2014.05.020 pmid: 25254342
30 Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463(7284): 1035–1041
doi: 10.1038/nature08797 pmid: 20107439
31 Sheng C, Zheng Q, Wu J, Xu Z, Wang L, Li W, Zhang H, Zhao XY, Liu L, Wang Z, Guo C, Wu HJ, Liu Z, Wang L, He S, Wang XJ, Chen Z, Zhou Q. Direct reprogramming of Sertoli cells into multipotent neural stem cells by defined factors. Cell Res 2012; 22(1): 208–218
doi: 10.1038/cr.2011.175 pmid: 22064700
32 Marro S, Pang ZP, Yang N, Tsai MC, Qu K, Chang HY, Südhof TC, Wernig M. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 2011; 9(4): 374–382
doi: 10.1016/j.stem.2011.09.002 pmid: 21962918
33 Ginsberg M, James D, Ding BS, Nolan D, Geng F, Butler JM, Schachterle W, Pulijaal VR, Mathew S, Chasen ST, Xiang J, Rosenwaks Z, Shido K, Elemento O, Rabbany SY, Rafii S. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFb suppression. Cell 2012; 151(3): 559–575
doi: 10.1016/j.cell.2012.09.032 pmid: 23084400
34 Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 2011; 475(7356): 386–389
doi: 10.1038/nature10116 pmid: 21562492
35 Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 2011; 475(7356): 390–393
doi: 10.1038/nature10263 pmid: 21716291
36 Forsberg M, Carlén M, Meletis K, Yeung MS, Barnabé-Heider F, Persson MA, Aarum J, Frisén J. Efficient reprogramming of adult neural stem cells to monocytes by ectopic expression of a single gene. Proc Natl Acad Sci USA 2010; 107(33): 14657–14661
doi: 10.1073/pnas.1009412107 pmid: 20675585
37 Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP. Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 2012; 318(13): 1528–1541
doi: 10.1016/j.yexcr.2012.02.040 pmid: 22426197
38 Wang L, Wang L, Huang W, Su H, Xue Y, Su Z, Liao B, Wang H, Bao X, Qin D, He J, Wu W, So KF, Pan G, Pei D. Generation of integration-free neural progenitor cells from cells in human urine. Nat Methods 2013; 10(1): 84–89
doi: 10.1038/nmeth.2283 pmid: 23223155
39 Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011; 13(3): 215–222
doi: 10.1038/ncb2164 pmid: 21278734
40 Kurian L, Sancho-Martinez I, Nivet E, Aguirre A, Moon K, Pendaries C, Volle-Challier C, Bono F, Herbert JM, Pulecio J, Xia Y, Li M, Montserrat N, Ruiz S, Dubova I, Rodriguez C, Denli AM, Boscolo FS, Thiagarajan RD, Gage FH, Loring JF, Laurent LC, Izpisua Belmonte JC. Conversion of human fibroblasts to angioblast-like progenitor cells. Nat Methods 2013; 10(1): 77–83
doi: 10.1038/nmeth.2255 pmid: 23202434
41 Li J, Huang NF, Zou J, Laurent TJ, Lee JC, Okogbaa J, Cooke JP, Ding S. Conversion of human fibroblasts to functional endothelial cells by defined factors. Arterioscler Thromb Vasc Biol 2013; 33(6): 1366–1375
doi: 10.1161/ATVBAHA.112.301167 pmid: 23520160
42 Li K, Zhu S, Russ HA, Xu S, Xu T, Zhang Y, Ma T, Hebrok M, Ding S. Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell 2014; 14(2): 228–236
doi: 10.1016/j.stem.2014.01.006 pmid: 24506886
43 Zhu S, Rezvani M, Harbell J, Mattis AN, Wolfe AR, Benet LZ, Willenbring H, Ding S. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 2014; 508(7494): 93–97
doi: 10.1038/nature13020 pmid: 24572354
44 Lumelsky N. Small molecules convert fibroblasts into islet-like cells avoiding pluripotent state. Cell Metab 2014; 19(4): 551–552
doi: 10.1016/j.cmet.2014.03.019 pmid: 24703689
45 Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 2012; 485(7400): 593–598
doi: 10.1038/nature11044 pmid: 22522929
46 Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 2010; 142(3): 375–386
doi: 10.1016/j.cell.2010.07.002 pmid: 20691899
47 Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 2008; 455(7213): 627–632
doi: 10.1038/nature07314 pmid: 18754011
48 Banga A, Akinci E, Greder LV, Dutton JR, Slack JM.In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proc Natl Acad Sci USA 2012; 109(38): 15336–15341
doi: 10.1073/pnas.1201701109 pmid: 22949652
49 Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 2012; 485(7400): 599–604
doi: 10.1038/nature11139 pmid: 22660318
50 Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Björklund A, Grealish S, Parmar M. Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci USA 2013; 110(17): 7038–7043
doi: 10.1073/pnas.1303829110 pmid: 23530235
51 Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 2013; 15(10): 1164–1175
doi: 10.1038/ncb2843 pmid: 24056302
52 Rouaux C, Arlotta P. Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. Nat Cell Biol 2013; 15(2): 214–221
doi: 10.1038/ncb2660 pmid: 23334497
53 Riddell J, Gazit R, Garrison BS, Guo G, Saadatpour A, Mandal PK, Ebina W, Volchkov P, Yuan GC, Orkin SH, Rossi DJ. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 2014; 157(3): 549–564
doi: 10.1016/j.cell.2014.04.006 pmid: 24766805
54 Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, Koch P, Brüstle O. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods 2012; 9(6): 575–578
doi: 10.1038/nmeth.1972 pmid: 22484851
55 Liu ML, Zang T, Zou Y, Chang JC, Gibson JR, Huber KM, Zhang CL. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun 2013; 4: 2183
pmid: 23873306
56 Kim YJ, Lim H, Li Z, Oh Y, Kovlyagina I, Choi IY, Dong X, Lee G. Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. Cell Stem Cell 2014; 15(4): 497–506
doi: 10.1016/j.stem.2014.07.013 pmid: 25158936
57 Zhu S, Ambasudhan R, Sun W, Kim HJ, Talantova M, Wang X, Zhang M, Zhang Y, Laurent T, Parker J, Kim HS, Zaremba JD, Saleem S, Sanz-Blasco S, Masliah E, McKercher SR, Cho YS, Lipton SA, Kim J, Ding S. Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res 2014; 24(1): 126–129
doi: 10.1038/cr.2013.156 pmid: 24296783
58 Lee JH, Mitchell RR, McNicol JD, Shapovalova Z, Laronde S, Tanasijevic B, Milsom C, Casado F, Fiebig-Comyn A, Collins TJ, Singh KK, Bhatia M. Single transcription factor conversion of human blood fate to NPCs with CNS and PNS developmental capacity. Cell Reports 2015; 11(9): 1367–1376
doi: 10.1016/j.celrep.2015.04.056 pmid: 26004181
59 Wang H, Cao N, Spencer CI, Nie B, Ma T, Xu T, Zhang Y, Wang X, Srivastava D, Ding S. Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Reports 2014; 6(5): 951–960
doi: 10.1016/j.celrep.2014.01.038 pmid: 24561253
60 Ifkovits JL, Addis RC, Epstein JA, Gearhart JD. Inhibition of TGFb signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS ONE 2014; 9(2): e89678
doi: 10.1371/journal.pone.0089678 pmid: 24586958
61 Boyd AW, Schrader JW. Derivation of macrophage-like lines from the pre-B lymphoma ABLS 8.1 using 5-azacytidine. Nature 1982; 297(5868): 691–693
doi: 10.1038/297691a0 pmid: 6178034
62 Cheng L, Hu W, Qiu B, Zhao J, Yu Y, Guan W, Wang M, Yang W, Pei G. Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res 2014; 24(6): 665–679
doi: 10.1038/cr.2014.32 pmid: 24638034
63 Han YC, Lim Y, Duffieldl MD, Li H, Liu J, Abdul Manaph NP, Yang M, Keating DJ, Zhou XF. Direct reprogramming of mouse fibroblasts to neural stem cells by small molecules. Stem Cells Int 2016; 2016: 4304916
doi: 10.1155/2016/4304916 pmid: 26788068
64 Mirakhori F, Zeynali B, Kiani S, Baharvand H. Brief azacytidine step allows the conversion of suspension human fibroblasts into neural progenitor-like cells. Cell J 2015; 17(1): 153–158
pmid: 25870845
65 Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G. Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 2015; 17(2): 204–212
doi: 10.1016/j.stem.2015.07.006 pmid: 26253202
66 Dai P, Harada Y, Takamatsu T. Highly efficient direct conversion of human fibroblasts to neuronal cells by chemical compounds. J Clin Biochem Nutr 2015; 56(3): 166–170
doi: 10.3164/jcbn.15-39 pmid: 26060345
67 Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, Chai Z, Zhao Y, Deng H. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 2015; 17(2): 195–203
doi: 10.1016/j.stem.2015.06.003 pmid: 26253201
68 Xu H, Wang Y, He Z, Yang H, Gao WQ. Direct conversion of mouse fibroblasts to GABAergic neurons with combined medium without the introduction of transcription factors or miRNAs. Cell Cycle 2015; 14(15): 2451–2460
doi: 10.1080/15384101.2015.1060382 pmid: 26114472
69 Cheng L, Gao L, Guan W, Mao J, Hu W, Qiu B, Zhao J, Yu Y, Pei G. Direct conversion of astrocytes into neuronal cells by drug cocktail. Cell Res 2015; 25(11): 1269–1272
doi: 10.1038/cr.2015.120 pmid: 26427716
70 Zhang L, Yin JC, Yeh H, Ma NX, Lee G, Chen XA, Wang Y, Lin L, Chen L, Jin P, Wu GY, Chen G. Small molecules efficiently reprogram human astroglial cells into functional neurons. Cell Stem Cell 2015; 17(6): 735–747
doi: 10.1016/j.stem.2015.09.012 pmid: 26481520
71 Zhang L, Li P, Hsu T, Aguilar HR, Frantz DE, Schneider JW, Bachoo RM, Hsieh J. Small-molecule blocks malignant astrocyte proliferation and induces neuronal gene expression. Differentiation 2011; 81(4): 233–242
doi: 10.1016/j.diff.2011.02.005 pmid: 21419563
72 Ghasemi-Kasman M, Hajikaram M, Baharvand H, Javan M. MicroRNA-mediated in vitro and in vivo direct conversion of astrocytes to neuroblasts. PLoS ONE 2015; 10(6): e0127878
doi: 10.1371/journal.pone.0127878 pmid: 26030913
73 Thoma EC, Merkl C, Heckel T, Haab R, Knoflach F, Nowaczyk C, Flint N, Jagasia R, Jensen Zoffmann S, Truong HH, Petitjean P, Jessberger S, Graf M, Iacone R. Chemical conversion of human fibroblasts into functional Schwann cells. Stem Cell Rep 2014; 3(4): 539–547
doi: 10.1016/j.stemcr.2014.07.014 pmid: 25358782
74 Park G, Yoon BS, Kim YS, Choi SC, Moon JH, Kwon S, Hwang J, Yun W, Kim JH, Park CY, Lim DS, Kim YI, Oh CH, You S. Conversion of mouse fibroblasts into cardiomyocyte-like cells using small molecule treatments. Biomaterials 2015; 54: 201–212
doi: 10.1016/j.biomaterials.2015.02.029 pmid: 25907053
75 Fu Y, Huang C, Xu X, Gu H, Ye Y, Jiang C, Qiu Z, Xie X. Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res 2015; 25(9): 1013–1024
doi: 10.1038/cr.2015.99 pmid: 26292833
76 Pennarossa G, Maffei S, Campagnol M, Tarantini L, Gandolfi F, Brevini TA. Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci USA 2013; 110(22): 8948–8953
doi: 10.1073/pnas.1220637110 pmid: 23696663
77 Pereyra-Bonnet F, Gimeno ML, Argumedo NR, Ielpi M, Cardozo JA, Giménez CA, Hyon SH, Balzaretti M, Loresi M, Fainstein-Day P, Litwak LE, Argibay PF. Skin fibroblasts from patients with type 1 diabetes (T1D) can be chemically transdifferentiated into insulin-expressing clusters: a transgene-free approach. PLoS ONE 2014; 9(6): e100369
doi: 10.1371/journal.pone.0100369 pmid: 24963634
78 Kanoh Y, Tomotsune D, Shirasawa S, Yoshie S, Ichikawa H, Yokoyama T, Mae S, Ito J, Mizuguchi M, Matsumoto K, Yue F, Sasaki K. In vitro transdifferentiation of HepG2 cells to pancreatic-like cells by CCl4, D-galactosamine, and ZnCl2. Pancreas 2011; 40(8): 1245–1252
doi: 10.1097/MPA.0b013e318221933d pmid: 21989025
79 Korac A, Cakic-Milosevic M, Ukropina M, Grubic M, Micunovic K, Petrovic V, Buzadzic B, Jankovic A, Vasilijevic A, Korac B. White adipocytes transdifferentiation into brown adipocytes induced by triiodothyronine. In: EMC 2008 14th European Microscopy Congress 1–5 September 2008, Aachen, Germany. Springer-Verlag Berlin Heidelberg, 2008:123–124
80 Moisan A, Lee YK, Zhang JD, Hudak CS, Meyer CA, Prummer M, Zoffmann S, Truong HH, Ebeling M, Kiialainen A, Gérard R, Xia F, Schinzel RT, Amrein KE, Cowan CA. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol 2015; 17(1): 57–67
doi: 10.1038/ncb3075 pmid: 25487280
81 Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F, Lu Y, Stanbouly S, Huang J, Rojas M, Vondriska TM, Stefani E, Deb A. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature 2014; 514(7524): 585–590
doi: 10.1038/nature13839 pmid: 25317562
82 Sayed N, Wong WT, Ospino F, Meng S, Lee J, Jha A, Dexheimer P, Aronow BJ, Cooke JP. Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity. Circulation 2015; 131(3): 300–309
doi: 10.1161/CIRCULATIONAHA.113.007394 pmid: 25359165
83 Brevini TA, Pennarossa G, Rahman MM, Paffoni A, Antonini S, Ragni G, deEguileor M, Tettamanti G, Gandolfi F. Morphological and molecular changes of human granulosa cells exposed to 5-azacytidine and addressed toward muscular differentiation. Stem Cell Rev 2014; 10(5): 633–642
doi: 10.1007/s12015-014-9521-4 pmid: 24858410
84 Nie T, Hui X, Gao X, Nie B, Mao L, Tang X, Yuan R, Li K, Li P, Xu A, Liu P, Ding S, Han W, Cooper GJ, Wu D. Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture. Biochem J 2015; 467(3): 487–494
doi: 10.1042/BJ20140727 pmid: 25730278
85 Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010; 7(5): 618–630
doi: 10.1016/j.stem.2010.08.012 pmid: 20888316
86 Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 2013; 341(6146): 651–654
doi: 10.1126/science.1239278 pmid: 23868920
87 Zhao Y, Zhao T, Guan J, Zhang X, Fu Y, Ye J, Zhu J, Meng G, Ge J, Yang S, Cheng L, Du Y, Zhao C, Wang T, Su L, Yang W, Deng H. A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming. Cell 2015; 163(7): 1678–1691
doi: 10.1016/j.cell.2015.11.017 pmid: 26686652
88 Ye J, Ge J, Zhang X, Cheng L, Zhang Z, He S, Wang Y, Lin H, Yang W, Liu J, Zhao Y, Deng H. Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res 2016; 26(1): 34–45
doi: 10.1038/cr.2015.142 pmid: 26704449
89 Long Y, Wang M, Gu H, Xie X. Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Res 2015; 25(10): 1171–1174
doi: 10.1038/cr.2015.96 pmid: 26251165
90 Li W, Li K, Wei W, Ding S. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 2013; 13(3): 270–283
doi: 10.1016/j.stem.2013.08.002 pmid: 24012368
91 Lin T, Wu S. Reprogramming with small molecules instead of exogenous transcription factors. Stem Cells Int 2015; 2015: 794632
doi: 10.1155/2015/794632 pmid: 25922608
92 Chen T, Yuan D, Wei B, Jiang J, Kang J, Ling K, Gu Y, Li J, Xiao L, Pei G. E-cadherin-mediated cell-cell contact is critical for induced pluripotent stem cell generation. Stem Cells 2010; 28(8): 1315–1325
doi: 10.1002/stem.456 pmid: 20521328
93 Feng B, Jiang J, Kraus P, Ng JH, Heng JC, Chan YS, Yaw LP, Zhang W, Loh YH, Han J, Vega VB, Cacheux-Rataboul V, Lim B, Lufkin T, Ng HH. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 2009; 11(2): 197–203
doi: 10.1038/ncb1827 pmid: 19136965
94 Cheng L. Novel strategy for treating neural disease. Sci China Life Sci 2014; 57(9): 947–948
doi: 10.1007/s11427-014-4686-2 pmid: 24935783
[1] Bao-Zhu Yuan,Junzhi Wang. The regulatory sciences for stem cell-based medicinal products[J]. Front. Med., 2014, 8(2): 190-200.
Full text