Table 1.
Chemicals used to enhance reprogramming efficiency or replace essential reprogramming factors.
| No. | Author /Year/Journal |
Title | Chemical Used | Details | Yamanaka Factor Used | Species and Cell Type | Inference | Ref. |
|---|---|---|---|---|---|---|---|---|
| 1 | Shi et al./2008a/Cell Stem Cell | A combined chemical and genetic approach for the generation of induced pluripotent stem cells | BIX01294 | G9a histone methyltransferase inhibitor | OK | mouse neural progenitor cells (mNPCs) | OK+BIX01294 enhances efficiency ~1.5 times more than OSKM and ~8 times more than OK; BIX01294 is able to replace S and M. | [60] |
| BIX01294 | G9a histone methyltransferase inhibitor | KSM | fetal neural progenitor cells (fNPCs) | BIX01294 is able to replace O in NPC reprogramming but with extremely low efficiency. | ||||
| 2 | Shi et al./2008b/Cell Stem Cell | Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds | BIX01294 | G9a histone methyltransferase inhibitor | OK | mouse embryonic fibroblasts (MEFs) | OK+BIX01294 enhances efficiency ~5 times more than OK and is able to replace S. | [61] |
| BayK8644 | L-type calcium channel agonist | OK | MEFs | OK+BIX01294+BayK8644 enhances efficiency ~15 times more than OK. | ||||
| RG108 | DNA methyltransferase (DNMT) inhibitor | OK | MEFs | OK+BIX01294+RG108 enhances reprogramming efficiency ~30 times more than OK. | ||||
| 3 | Mikkelsen et al./2008/Nature | Dissecting direct reprogramming through integrative genomic analysis | AZA | DNMT inhibitor | OSKM | MEFs | AZA treatment during days 8–10 resulted in a ~4-fold increase in efficiency compared with untreated controls. | [62] |
| 4 | Huangfu et al./2008a/Nature Biotechnology | Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds | VPA | histone deacetylase (HDAC) inhibitor | OSKM | MEFs | More than 100-fold increase in efficiency with OSKM. | [63] |
| AZA | DNMT inhibitor | OSK | MEFs | ~3-fold increase in efficiency with OSK. | ||||
| VPA | HDAC inhibitor | OSK | MEFs | ~50-fold increase in efficiency with OSK. | ||||
| Dexamethasone (dex) | synthetic glucocorticoid | OSKM | MEFs | Improved the effect of 5′-azaC by 2.6-fold when used in combination, even though dex alone had no significant effect. | ||||
| TSA | HDAC inhibitor | OSKM | MEFs | ~15-fold increase in efficiency with OSKM. | ||||
| SAHA | HDAC inhibitor | OSKM | MEFs | ~2-fold increase in efficiency with OSKM. | ||||
| 5 | Huangfu et al./2008b/Nature Biotechnology | Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2 | VPA | HDAC inhibitor | OSK | human fibroblasts | 10- to 20-fold increase compared with OSK (reprogramming efficiency 1.1%). | [64] |
| VPA | HDAC inhibitor | OS | human fibroblasts | VPA is able to replace K and M (reprogramming efficiency 0.001%). | ||||
| 6 | Silva et al./2008/PLOS Biology | Promotion of reprogramming to ground state pluripotency by signal inhibition | PD0325901 + CHIR99021 (2i) | inhibitors of MEK and GSK3, respectively | OK | MEFs | Together with LIF, it promotes ground state pluripotency in OK pre-iPSCs | [65] |
| 7 | Li W et al./2009/Cell Stem Cell | Generation of rat and human-induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors | PD0325901 + CHIR99021 (2i) + A-83-01 | Inhibitors of MEK, GSK3, and TGF-b1(ALK5), respectively | OSK | rat liver epithelial cells | Together with LIF and 2i, they generate mESC-like rat iPSCs | [66] |
| PD0325901 + CHIR99021 (2i) + A-83-01 | inhibitor of MEK, GSK3, and TGF-b1(ALK5) respectively | OSK | human fibroblasts | Together with LIF and 2i, they generate mESC-like human iPSCs | ||||
| 8 | Li et al./2011/Cell Research | Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules | VC6T | VPA, CHIR99021, 616452, tranylcypromine | O | mouse fibroblasts | A specific chemical combination that is sufficient to permit reprogramming from mouse embryonic and adult fibroblasts in the presence of a single transcription factor (Oct4) within 20 days, replacing Sox2, Klf4, and c-Myc. | [56] |
| 9 | Hou et al./2013/Science | Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds | VC6TF | VPA, CHIR99021, 616452, tranylcypromine, forskolin | None | Oct4 promoter-driven GFP expression (OG)-MEFs | A GFP-positive cluster was generated using VC6TF on day 20 (D20) after chemical treatment. The expression of two pluripotency-related genes, Sall4 and Sox2, and the expression of several extraembryonic endoderm (XEN) markers, Gata4, Gata6, and Sox17 were significantly induced by VC6TF. | [57] |
| VC6TFZ | VPA, CHIR99021, 616452, tranylcypromine, forskolin, DZNep | None | OG-MEFs | Morphology of a compact, epithelioid, GFP-positive colony on day 32 (D32) after treatment | ||||
| VC6TFZ with 2i-medium | VC6TFZ + 2i-medium | None | OG-MEFs | 2i-competent, ESC-like, and GFP-positive cells obtained as chemically induced pluripotent stem cells (CiPSCs). | ||||
| 10 | Zhao et al./2015/Cell | A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming | VC6TFZASD with N2B27-2iL | VPA, CHIR99021, 616452, tranylcypromine, forskolin, DZNep, AM580, SGC0946, 5-aza-dC + N2B27-2i medium + LIF | None | MEFs | The XEN-like state allows us to identify small-molecule boosters and establish a robust chemical reprogramming system with a yield ~1000-fold greater than that of the previously reported protocol. | [67] |
| 11 | Li X et al./2017/Cell Stem Cell | Direct reprogramming of fibroblasts via achemically induced XEN-like state | VC6TFAE | VPA, TD114-2/CHIR99021, 616452, tranylcypromine, forskolin, AM580, EPZ004777 | None | MEFs, mouse postnatal fibroblasts (NBFs), and mouse adult lung fibroblasts (MAFs) | Functional neurons and hepatocytes can be induced from fibroblasts via a chemically induced and highly expandable XEN-like state, bypassing the pluripotent stage.Chemical induction increases the expression of XEN master genes (Gata4, Sall4, Sox17, and Gata6). | [59] |
| 12 | Guan et al./2022/Nature | Chemical reprogramming of human somatic cells to pluripotent stem cells | C6NYSA | CHIR99021, 616452, TTNPB, Y27632, SAG, ABT869 | None | human embryonic fibroblasts (HEFs) | A cocktail of small molecules (CHIR99021, 616452, and TTNPB) converts human fibroblasts into epithelial-like cells. Additional small molecules (Y27632, ABT869, and SAG) further promoted the formation of epithelial-like cells. | [68] |
| 13 | Yang et al./2023/Aging | Chemically induced reprogramming to reverse cellular aging | VC6TF | VPA, CHIR99021, 616452, tranylcypromine, forskolin | None | mouse fibroblasts | Rejuvenation through age reversal can be achieved not only genetically but also chemically.Within a week, a cocktail of six chemicals succeeded in restoring the whole-genome transcriptional profile characteristic of youth and reversed transcriptional age without compromising cellular identity. | [58] |
| C6NYSA | CHIR99021, 616452, TTNPB, Y27632, SAG, ABT869 | None | human fibroblasts |
Abbreviations: MEFs, mouse embryonic fibroblasts; HEFs, human embryonic fibroblasts; LIF, leukemia inhibitory factor; mESC, mouse embryonic stem cell; GFP, green fluorescent protein; OG, Oct4 promoter-driven GFP expression; XEN, extraembryonic endoderm; DNMT, DNA methyltransferase; HDAC, histone deacetylase; V, valpronic acid (VPA); C, a GSK3-β inhibitor (CHIR99021); 6, a TGF-β inhibitor (616452); T, LSD1 inhibitor (Tranylcypromine); F, Forskolin (FSK); Z, SAH hydrolase inhibitor (3-deazaneplanocin, DZNep); 2i, GSK and MAPK inhibition; N, Retinoic Acid Receptor (RAR) Agonist (TTNPB); A, an RAR agonist (AM580); S, a DOT1L inhibitor (SGC0946); D, 5-aza-dC; S, Smoothened Agonist (SAG) HCI; A, ABT869 (Linifanib, RTK inhibitor); TD114-2, a preferable GSK3-β inhibitor; E, a DOT1L inhibitor (EPZ004777).