Direct reprogramming of mouse fibroblasts into hepatocyte-like cells by polyethyleneimine-modified nanoparticles through epigenetic activation of hepatic transcription factors

2020 ◽  
Vol 17 ◽  
pp. 100281
Author(s):  
M. Wang ◽  
J. Yu ◽  
L. Cai ◽  
X. Yang
Keyword(s):  
Transcription Factors ◽  
Direct Reprogramming ◽  
Mouse Fibroblasts

Abstract P493: Histone Reader PHF7 Cooperates With The SWI/SNF Complex At Cardiac Super Enhancers To Promote Direct Reprogramming

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
Kenian Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cardiac Fibroblasts ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Direct Reprogramming ◽  
Ischemic Disease ◽  
Treat Heart Failure ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Ischemic heart disease is the leading cause of death worldwide. Direct reprogramming of resident cardiac fibroblasts (CFs) to induced cardiomyocytes (iCLMs) has emerged as a potential therapeutic approach to treat heart failure and ischemic disease. Cardiac reprogramming was first achieved through forced expression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT); our laboratory found that Hand2 (GHMT) and Akt1 (AGHMT) markedly enhanced reprogramming efficiency in embryonic and postnatal cell types. However, adult mouse and human fibroblasts are resistant to reprogramming due to staunch epigenetic barriers. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the epigenetic reader PHF7 as the most potent activating factor. We validated the findings of this screen and found that PHF7 augmented reprogramming of adult fibroblasts ten-fold. Mechanistically, PHF7 localized to cardiac super enhancers in fibroblasts by reading H3K4me2 marks, and through cooperation with the SWI/SNF complex, increased chromatin accessibility and transcription factor binding at these multivalent enhancers. Further, PHF7 recruited cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieved efficient reprogramming through these mechanisms in the absence of Gata4. Collectively, these studies highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

scholarly journals Chemical compound-based direct reprogramming for future clinical applications

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Yukimasa Takeda ◽  
Yoshinori Harada ◽  
Toshikazu Yoshikawa ◽  
Ping Dai
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Chemical Compound ◽  
Chemical Compounds ◽  
Cell Types ◽  
Direct Reprogramming ◽  
Cell Type ◽  
Promising Alternative ◽  
Cell Functions ◽  
Transplantation Therapy

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy.

scholarly journals Direct Reprogramming of Mouse Fibroblasts to Neural Stem Cells by Small Molecules

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yan-Chuang Han ◽  
Yoon Lim ◽  
Michael D. Duffieldl ◽  
Hua Li ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Neural Stem Cells ◽  
Small Molecules ◽  
Clinical Medicine ◽  
Viral Vector ◽  
Expression Patterns ◽  
Tumor Formation ◽  
Patient Specific ◽  
Mouse Fibroblasts

Although it is possible to generate neural stem cells (NSC) from somatic cells by reprogramming technologies with transcription factors, clinical utilization of patient-specific NSC for the treatment of human diseases remains elusive. The risk hurdles are associated with viral transduction vectors induced mutagenesis, tumor formation from undifferentiated stem cells, and transcription factors-induced genomic instability. Here we describe a viral vector-free and more efficient method to induce mouse fibroblasts into NSC using small molecules. The small molecule-induced neural stem (SMINS) cells closely resemble NSC in morphology, gene expression patterns, self-renewal, excitability, and multipotency. Furthermore, the SMINS cells are able to differentiate into astrocytes, functional neurons, and oligodendrocytesin vitroandin vivo. Thus, we have established a novel way to efficiently induce neural stem cells (iNSC) from fibroblasts using only small molecules without altering the genome. Such chemical induction removes the risks associated with current techniques such as the use of viral vectors or the induction of oncogenic factors. This technique may, therefore, enable NSC to be utilized in various applications within clinical medicine.

scholarly journals Direct reprogramming of human fibroblasts into insulin-producing cells by transcription factors

2021 ◽  
Author(s):  
Rosa Gasa ◽  
Marta Fontcuberta-PiSunyer ◽  
Ainhoa García-Alamán ◽  
Élia Prades ◽  
Noèlia Téllez ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Somatic Cell ◽  
Human Fibroblasts ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Skin Fibroblasts ◽  
Direct Reprogramming ◽  
Β Cell ◽  
Insulin Producing Cells

Direct lineage reprogramming of one somatic cell into another bypassing an intermediate pluripotent state has emerged as an alternative to embryonic or induced pluripotent stem cell differentiation to generate clinically relevant cell types. One cell type of clinical interest is the pancreatic β cell that secretes insulin and whose loss and/or dysfunction leads to diabetes. Generation of functional β-like cells from developmentally related somatic cell types (pancreas, liver, gut) has been achieved via enforced expression of defined sets of transcription factors. However, clinical applicability of these findings is challenging because the starting cell types are not easily obtainable. Skin fibroblasts are accessible and easily manipulated cells that could be a better option, but available studies indicate that their competence to give rise to β cells through similar direct reprogramming approaches is limited. Here, using human skin fibroblasts and a protocol that ensures high and consistent expression of adenovirus-encoded reprogramming factors, we show that the transcription factor cocktail consisting of Pdx1, Ngn3, MafA, Pax4 and Nkx2-2 activates key β cell genes and down-regulates the fibroblast transcriptional program. The converted cells produce insulin and exhibit intracellular calcium responses to glucose and/or membrane depolarization. Furthermore, they secrete insulin in response to glucose in vitro and after transplantation in vivo. These findings demonstrate that transcription factor-mediated direct reprogramming of human fibroblasts is a feasible strategy to generate insulin-producing cells.

scholarly journals Direct somatic lineage conversion

2015 ◽  
Vol 370 (1680) ◽  
pp. 20140368 ◽  
Author(s):  
Koji Tanabe ◽  
Daniel Haag ◽  
Marius Wernig
Keyword(s):  
Transcription Factors ◽  
Cell Types ◽  
Nuclear Transplantation ◽  
Specific Cell ◽  
Direct Reprogramming ◽  
Cell Type ◽  
Mesodermal Cell ◽  
Related Cell ◽  
Transplantation Experiments ◽  
Cell Specialization

The predominant view of embryonic development and cell differentiation has been that rigid and even irreversible epigenetic marks are laid down along the path of cell specialization ensuring the proper silencing of unrelated lineage programmes. This model made the prediction that specialized cell types are stable and cannot be redirected into other lineages. Accordingly, early attempts to change the identity of somatic cells had little success and was limited to conversions between closely related cell types. Nuclear transplantation experiments demonstrated, however, that specialized cells even from adult mammals can be reprogrammed into a totipotent state. The discovery that a small combination of transcription factors can reprogramme cells to pluripotency without the need of oocytes further supported the view that these epigenetic barriers can be overcome much easier than assumed, but the extent of this flexibility was still unclear. When we showed that a differentiated mesodermal cell can be directly converted to a differentiated ectodermal cell without a pluripotent intermediate, it was suggested that in principle any cell type could be converted into any other cell type. Indeed, the work of several groups in recent years has provided many more examples of direct somatic lineage conversions. Today, the question is not anymore whether a specific cell type can be generated by direct reprogramming but how it can be induced.

Direct Reprogramming of Mouse Fibroblasts into Pulmonary Epithelial-Like Cells

2019 ◽  
Author(s):  
T. Kusumoto ◽  
M. Ishii ◽  
M. Yotsukura ◽  
A.E. Hegab ◽  
F. Saito ◽  
...  
Keyword(s):  
Direct Reprogramming ◽  
Mouse Fibroblasts

scholarly journals Yorkie and JNK revert syncytial muscles into myoblasts during Org-1–dependent lineage reprogramming

2019 ◽  
Vol 218 (11) ◽  
pp. 3572-3582 ◽  
Author(s):  
Christoph Schaub ◽  
Marcel Rose ◽  
Manfred Frasch
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activators ◽  
Direct Reprogramming ◽  
Research Attention ◽  
Lineage Reprogramming ◽  
Adult Drosophila ◽  
Alary Muscles ◽  
Shed Light

Lineage reprogramming has received increased research attention since it was demonstrated that lineage-restricted transcription factors can be used in vitro for direct reprogramming. Recently, we reported that the ventral longitudinal musculature of the adult Drosophila heart arises in vivo by direct lineage reprogramming from larval alary muscles, a process that starts with the dedifferentiation and fragmentation of syncytial muscle cells into mononucleate myoblasts and depends on Org-1 (Drosophila Tbx1). Here, we shed light on the events occurring downstream of Org-1 in this first step of transdifferentiation and show that alary muscle lineage-specific activation of Yorkie plays a key role in initiating the dedifferentiation and fragmentation of these muscles. An additional necessary input comes from active dJNK signaling, which contributes to the activation of Yorkie and furthermore activates dJun. The synergistic activities of the Yorkie/Scalloped and dJun/dFos transcriptional activators subsequently initiate alary muscle fragmentation as well as up-regulation of Myc and piwi, both crucial for lineage reprogramming.

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