Pharmacologic fibroblast reprogramming into photoreceptors restores vision

Mahato, Biraj; Kaya, Koray Dogan; Fan, Yan; Sumien, Nathalie; Shetty, Ritu A.; Zhang, Wei; Davis, Delaney L; Möck, Thomas; Batabyal, Subrata; Ni, Aiguo; Mohanty, Samarendra; Han, Zongchao; Farjo, Rafal; Forster, Michael J.; Swaroop, Anand; Chavala, Sai H.

doi:10.1038/s41586-020-2201-4

Cited by 83 publications

(65 citation statements)

References 47 publications

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“…After that, neural stem cell core regulators network was built up, which was reminiscent of a specification process. Besides, the molecular dynamics during the chemical reprogramming from fibroblast to photoreceptor-like cells (CiPCs) was probably initiated by the activation of photoreceptor-specifying transcription factors, such as Rorb , Ascl1 and Pias3 , reminiscent of a priming phase 20 . The stepwise manner in the activation of the master transcription factors suggested identifying the key molecular events in a chemical reprogramming process could help to optimize the protocol in a stepwise manner to achieve higher efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, since the chemicals C, 6, F, and their combinations have been widely used in different chemical reprogramming systems and generate many different cell fates 8 , 12 , 13 , 15 – 17 , 19 , 20 , it is still unclear whether Sox17 activation is a specific outcome of the chemical treatment and whether these chemicals can prime the cells and facilitate cell fate conversion into other lineages simultaneously. These are some of the questions we intend to address in our future study.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, chemical reprogramming strategies have been extended to inducing direct cell lineage conversion into functional cell types without an intermediate pluripotent state. For instance, neural progenitors 10 , functional neurons 11 , 12 , cardiomyocytes 13 , 14 , skeletal muscles 15 , brown adipocytes 16 , 17 , astrocytes 18 , endoderm progenitor-like cells 19 , and photoreceptor-like cells 20 are reported to be induced from fibroblasts with chemicals alone. Besides, endoderm progenitor cells are induced from gut epithelium with pure chemicals 21 , and human fetal astrocytes are converted into functional neurons by chemical combinations 22 .…”

Section: Introductionmentioning

confidence: 99%

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Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

Yang

et al. 2020

Commun Biol

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Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state. However, it is elusive how the chemicals orchestrate the cell fate alteration. In this study, we analyze molecular dynamics in chemical reprogramming from fibroblasts to a XEN-like state. We find that Sox17 is initially activated by the chemical cocktails, and XEN cell fate specialization is subsequently mediated by Sox17 activated expression of other XEN master genes, such as Sall4 and Gata4. Furthermore, this stepwise process is differentially regulated. The core reprogramming chemicals CHIR99021, 616452 and Forskolin are all necessary for Sox17 activation, while differently required for Gata4 and Sall4 expression. The addition of chemical boosters in different phases further improves the generation efficiency of XEN-like cells. Taken together, our work demonstrates that chemical reprogramming is regulated in 3 distinct “prime–specify–transit” phases initiated with endogenous Sox17 activation, providing a new framework to understand cell fate determination.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

Yang

et al. 2020

Commun Biol

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“…As a favorable method, stem cell therapy could substitute for the loss of retinal neurons [ 50 , 51 ]. Recently, Chavala's team reported five small molecules (VPA, CHIR99021, RepSox, Forskolin, and IWR1) were able to transdifferentiate fibroblasts into photoreceptor-like cells [ 52 ]. The authors also confirmed that CiPCs could mend pupil reflex and vision when transplanted into the subretinal space of mice with retinal degeneration.…”

Section: Transdifferentiation In Vitromentioning

confidence: 99%

Small Molecule Epigenetic Modulators in Pure Chemical Cell Fate Conversion

Yuan

Zhu

Liu

et al. 2020

Stem Cells International

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Although innovative technologies for somatic cell reprogramming and transdifferentiation provide new strategies for the research of translational medicine, including disease modeling, drug screening, artificial organ development, and cell therapy, recipient safety remains a concern due to the use of exogenous transcription factors during induction. To resolve this problem, new induction approaches containing clinically applicable small molecules have been explored. Small molecule epigenetic modulators such as DNA methylation writer inhibitors, histone methylation writer inhibitors, histone acylation reader inhibitors, and histone acetylation eraser inhibitors could overcome epigenetic barriers during cell fate conversion. In the past few years, significant progress has been made in reprogramming and transdifferentiation of somatic cells with small molecule approaches. In the present review, we systematically discuss recent achievements of pure chemical reprogramming and transdifferentiation.

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“…More recently, Mahato et al showed that fibroblasts can be chemically reprogrammed into rod photoreceptors using a set of small molecules—valproic acid, CHIR99021, RepSox, forskolin, SHH, taurine, and RA. Notably, transplantation of the reprogramed photoreceptors resulted in improvement in visual functions in a mouse degenerative model [ 102 ], which highlighted the therapeutic potential of this direct reprogramming strategy in treating blinding retinal diseases.…”

Section: Alternative Direct Reprogramming Approaches Using Micrornmentioning

confidence: 99%

Neuronal Reprogramming for Tissue Repair and Neuroregeneration

Liou

Edwards

Martin

et al. 2020

IJMS

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Stem cell and cell reprogramming technology represent a rapidly growing field in regenerative medicine. A number of novel neural reprogramming methods have been established, using pluripotent stem cells (PSCs) or direct reprogramming, to efficiently derive specific neuronal cell types for therapeutic applications. Both in vitro and in vivo cellular reprogramming provide diverse therapeutic pathways for modeling neurological diseases and injury repair. In particular, the retina has emerged as a promising target for clinical application of regenerative medicine. Herein, we review the potential of neuronal reprogramming to develop regenerative strategy, with a particular focus on treating retinal degenerative diseases and discuss future directions and challenges in the field.

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Pharmacologic fibroblast reprogramming into photoreceptors restores vision

Cited by 83 publications

References 47 publications

Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

Small Molecule Epigenetic Modulators in Pure Chemical Cell Fate Conversion

Neuronal Reprogramming for Tissue Repair and Neuroregeneration

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