Hypoxia Enhances Direct Reprogramming of Mouse Fibroblasts to Cardiomyocyte-Like Cells

Wang, Yanyan; Shi, Shujun; Liu, Huiwen; Li, Meng

doi:10.1089/cell.2015.0051

Cited by 14 publications

(15 citation statements)

References 21 publications

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“…Wang et al (126) showed that hypoxic preconditioning of mouse neonatal tail fibroblasts at 2% O 2 for 6 h increased the frequency of GMT-induced aMHC + iCMs .10-fold to Similarly, Yoo et al (113) applied nanopatterned, gelatin-coated, polyurethane acrylate substrates to increase efficiency and speed of GMT-induced cardiac conversion in mouse fibroblasts. Mechanistically, nanotopographic cues enhanced mechanotransduction through up-regulation of focal adhesion kinase and its target genes and led to epigenetic repatterning through accumulation of permissive H3K4me3 histone marks at gene loci known to be active in CMs.…”

Section: Using Chemically Defined Serum-free Culture Conditionsmentioning

confidence: 99%

Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies

2018

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To date, no viable therapeutic options exist for the effective and sustained reversal of cardiac failure, other than heart transplantation and mechanical circulatory assist devices. Therefore, divergent strategies aiming at the de novo formation of contractile tissue, as a prerequisite for the restoration of cardiac pump function, are currently being pursued. Clinical trials involving the transplantation of somatic progenitor cells failed. The search for alternative cell-based strategies to combat the consequences of ischemic injury has sparked widespread interest in the genetic and pharmacologic reprogramming of fibroblasts into cardiomyocytes, harnessing the abundant in vivo pool of cardiac fibroblasts. Here, we provide a comprehensive overview of in vitro and in vivo cardiac reprogramming studies identified in an extensive literature search. We systematically review and evaluate feasibility, efficiency, and reproducibility of the different technologies currently being explored. Finally, we discuss potential safety issues deduced from preclinical studies and identify obstacles that must be overcome before clinical translation.-Klose, K., Gossen, M., Stamm, C. Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies.

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Section: Using Chemically Defined Serum-free Culture Conditionsmentioning

confidence: 99%

Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies

2018

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“…In comparison with normoxic conditions, HIF-1α expression slightly increased during the two first weeks and then returned to normal levels. Although these researchers did not achieve fully reprogrammed functional iCMs, their study shed light on the effect of microenvironment factors on cardiac reprogramming [46]. Very recently, it has been demonstrated that hypoxia increases genomewide epigenetic bivalency (H3K4me3 and H3K27me3) in breast cancer [84].…”

Section: Hypoxiamentioning

confidence: 99%

“…According to the various important roles of oxygen in CM generation and function, oxygen appeared to affect direct cardiac reprogramming. Recently, Wang et al reported that a short term pretreatment of neonatal mouse dermal fibroblasts with low levels (2%) of oxygen for 6 h improved the efficiency of GMT-based cardiac reprogramming ( Table 2) [46]. They showed that hypoxic pretreatment for 6 h increased the efficiency of Myh6+ and cTnI+ cell generation by 10and 2.0-fold, respectively.…”

Section: Hypoxiamentioning

confidence: 99%

Boosters and barriers for direct cardiac reprogramming

2017

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Heart disease is currently the most significant cause of morbidity and mortality worldwide, which accounts for approximately 33% of all deaths. Recently, a promising and alchemy-like strategy has been developed called direct cardiac reprogramming, which directly converts somatic cells such as fibroblasts to cardiac lineage cells such as cardiomyocytes (CMs), termed induced CMs or iCMs. The first in vitro cardiac reprogramming study, mediated by cardiac transcription factors (TFs) -Gata4, Tbx5 and Mef2C-, was not enough efficient to produce an adequate number of fully reprogrammed, functional iCMs. As a result, numerous combinations of cardiac TFs exist for direct cardiac reprogramming of mouse and human fibroblasts. However, the efficiency of direct cardiac reprogramming remains low. Recently, a number of cellular and molecular mechanisms have been identified to increase the efficiency of direct cardiac reprogramming and the quality of iCMs. For example, microgrooved substrate, cardiogenic growth factors [VEGF, FGF, BMP4 and Activin A], and an appropriate stoichiometry of TFs boost the direct cardiac reprogramming. On the other hand, serum, TGFβ signaling, activators of epithelial to mesenchymal transition, and some epigenetic factors (Bmi1 and Ezh2) are barriers for direct cardiac reprogramming. Manipulating these mechanisms by the application of boosters and removing barriers can increase the efficiency of direct cardiac reprogramming and possibly make iCMs reliable for cell-based therapy or other potential applications. In this review, we summarize the latest trends in cardiac TF-or miRNA-based direct cardiac reprogramming and comprehensively discuses all molecular and cellular boosters and barriers affecting direct cardiac reprogramming.3

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“…It has been reported that hypoxic pretreatment of newborn mouse dermal fibroblasts for 6 h can improve the efficiency of iCM reprogramming [41]. Especially, a two-fold increase in cardiac troponin I (cTnI) expression and cTnt has been observed.…”

Section: Cardiac Reprogramming Involves Key Processes In Cardiogenmentioning

confidence: 99%

Improving cardiac reprogramming for heart regeneration

Liu

Lei

Wang³

2016

Current Opinion in Organ Transplantation

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Purpose of review Cardiovascular disease (CVD) is the leading cause of death in the world today, and the death rate has remained virtually unchanged in the last twenty years (American Heart Association). This severe life threatening disease underscores a critical need for developing novel therapeutic strategies to effectively treat this devastating disease. Cell-based therapy represents an extremely promising approach. Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers an attractive novel strategy for in situ heart regeneration. Major challenges of iCM reprogramming include the low conversion rate and heterogeneity of the iCMs. This review will summarize the major advancements in improving the iCM reprogramming efficiency and iCM maturation. Recent findings Numerous studies have been published in the past 18 months to describe various strategies for achieving more efficient iCM reprogramming. These strategies are based on our understanding of the molecular mechanisms of cardiogenesis, which include transcriptional networks, signaling pathways, and epigenetic cell fate change. Summary Novel strategies for highly efficient iCM reprogramming will be required for applying iCM reprogramming to patients. Creative and combined methods based on our understanding of cardiogenesis will continue to contribute heavily in the advancement of iCM reprogramming. We are highly optimistic that iCM reprogramming based heart therapy will restore the pumping function of damaged patient hearts.

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Hypoxia Enhances Direct Reprogramming of Mouse Fibroblasts to Cardiomyocyte-Like Cells

Cited by 14 publications

References 21 publications

Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies

Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies

Boosters and barriers for direct cardiac reprogramming

Improving cardiac reprogramming for heart regeneration

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