Tgfβ Signal Inhibition Cooperates in the Induction of iPSCs and Replaces Sox2 and cMyc
Open accessAbstract
Ectopic expression of Oct4, Sox2, cMyc, and Klf4 confers a pluripotent state upon several differentiated cell types, generating induced pluripotent stem cells (iPSCs) [1-8]. iPSC derivation is highly inefficient, and the underlying mechanisms are largely unknown. This low efficiency suggests the existence of additional cooperative factors whose identification is critical for understanding reprogramming. In addition, the therapeutic use of iPSCs relies on the development of efficient nongenetic means of factor delivery, and although a handful of replacement molecules have been identified, their use yields a further reduction to the already low reprogramming efficiency [9-11]. Thus, the identification of compounds that enhance rather than solely replace the function of the reprogramming factors will be of great use. Here, we demonstrate that inhibition of Tgfbbeta signaling cooperates in the reprogramming of murine fibroblasts by enabling faster, more efficient induction of iPSCs, whereas activation of Tgfbeta signaling blocks reprogramming. In addition to exhibiting a strong cooperative effect, the Tgfbeta receptor inhibitor bypasses the requirement for exogenous cMyc or Sox2, highlighting its dual role as a cooperative and replacement factor. The identification of a highly characterized pathway operating in iPSC induction will open new avenues for mechanistic dissection of the reprogramming process.
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E-616452 (RepSox) is a TGF-β inhibitor that has been used to replace SOX2 during epigenetic reprogramming.
“E-616452, also known as RepSox, is a TGF-β inhibitor that has been used in experiments to replace SOX2 during epigenetic reprogramming [68, 69].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [69]
Experimental Procedures (Cell culture and iPSC induction; page unavailable) identifies the inhibitor used as Calbiochem/EMD 616452. Results and Discussion (page unavailable) reports that the inhibitor enabled Sox2 replacement during iPSC reprogramming. Our copy does not identify 616452 by the name RepSox, so it does not verify that alias. (LLM, conf=0.88)
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- Authors
- Maherali, N., & Hochedlinger, K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hochedlinger, Konrad
- ORCID
- Hochedlinger, Konrad
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 19
- Issue
- 20
- Pages
- 1718-1723
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC3538372
- OpenAlex
- W2030299771
- Cited by
- 348
- References
- 24
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 14 · 2020: 9 · 2019: 15 · 2018: 18 · 2017: 12 · 2016: 26 · 2015: 30 · 2014: 40 · 2013: 29 · 2012: 36
- FWCI
- 16.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1dp2od003266-01)
- Natural Sciences and Engineering Research Council of Canada
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD058013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- induced pluripotent stem cells, TGF-beta signaling, TGF-β receptor inhibition, cellular reprogramming, SOX2, c-Myc, Oct4, KLF4, fibroblast reprogramming, reprogramming efficiency
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Kruppel-Like Factor 4, Animals, Cell Differentiation, Cell Line, Signal Transduction, Transforming Growth Factor beta, Proto-Oncogene Proteins c-myc, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Cell Culture Techniques, Protein Kinase Inhibitors, Mice, SOXB1 Transcription Factors, Induced Pluripotent Stem Cells
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