scholarly journals MicroRNA-Mediated Direct Reprogramming of Human Adult Fibroblasts Toward Cardiac Phenotype

2020 ◽  
Vol 8 ◽  
Author(s):  
C. Paoletti ◽  
C. Divieto ◽  
G. Tarricone ◽  
F. Di Meglio ◽  
D. Nurzynska ◽  
...  
Keyword(s):  
Direct Reprogramming ◽  
Human Adult ◽  
Cardiac Phenotype ◽  
Adult 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 Generation of iPSC line HEL47.2 from healthy human adult fibroblasts

2015 ◽  
Vol 15 (1) ◽  
pp. 263-265 ◽  
Author(s):  
Ras Trokovic ◽  
Jere Weltner ◽  
Timo Otonkoski
Keyword(s):  
Ipsc Line ◽  
Healthy Human ◽  
Human Adult ◽  
Adult Fibroblasts

scholarly journals Reprogramming Human Adult Fibroblasts into GABAergic Interneurons

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3450
Author(s):  
Andreas Bruzelius ◽  
Srisaiyini Kidnapillai ◽  
Janelle Drouin-Ouellet ◽  
Tom Stoker ◽  
Roger A. Barker ◽  
...  
Keyword(s):  
Human Fibroblasts ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Gabaergic Interneurons ◽  
Human Adult ◽  
Gene And Protein Expression ◽  
Parkinson’S Diseases ◽  
Fetal Fibroblasts ◽  
Adult Skin ◽  
Adult Fibroblasts

Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders.

scholarly journals MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts

2018 ◽  
Vol 46 (1) ◽  
pp. 73-84.e7 ◽  
Author(s):  
Seong Won Lee ◽  
Young Mi Oh ◽  
Ya-Lin Lu ◽  
Woo Kyung Kim ◽  
Andrew S. Yoo
Keyword(s):  
Cell Fate ◽  
Human Adult ◽  
Neuronal Conversion ◽  
Adult Fibroblasts
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