Boosters and barriers for direct cardiac reprogramming

Talkhabi, Mahmood; Zonooz, Elmira Rezaei; Baharvand, Hossein

doi:10.1016/j.lfs.2017.04.013

Cited by 10 publications

(10 citation statements)

References 112 publications

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“…Molecular machinery that controls epigenetic changes of chromatin contributes to cell differentiation and reprogramming . We reason that it may play an important role in PNEC transdifferentiation.…”

Section: Resultsmentioning

confidence: 99%

Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury

Yao

Lin

et al. 2017

Stem Cells

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Production of an appropriate number of distinct cell types in precise locations during embryonic development is critical for proper tissue function. Homeostatic renewal or repair of damaged tissues in adults also requires cell expansion and transdifferentiation to replenish lost cells. However, the responses of diverse cell types to tissue injury are not fully elucidated. Moreover, the molecular mechanisms underlying transdifferentiation remain poorly understood. This knowledge is essential for harnessing the regenerative potential of individual cell types. This study investigated the fate of pulmonary neuroendocrine cells (PNECs) following lung damage to understand their plasticity and potential. PNECs are proposed to carry out diverse physiological functions in the lung and can also be the cells of origin of human small cell lung cancer. We found that Notch signaling is activated in proliferating PNECs in response to epithelial injury. Forced induction of high levels of Notch signaling in PNECs in conjunction with lung injury results in extensive proliferation and transdifferentiation of PNECs toward the fate of club cells, ciliated cells and goblet cells. Conversely, inactivating Notch signaling in PNECs abolishes their ability to switch cell fate following lung insult. We also established a connection between PNEC transdifferentiation and epigenetic modification mediated by the polycomb repressive complex 2 and inflammatory responses that involve the IL6-STAT3 pathway. These studies not only reveal a major pathway that controls PNEC fate change following lung injury but also provide tools to uncover the molecular basis of cell proliferation and fate determination in response to lung injury. Stem Cells 2018;36:377-391.

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Section: Resultsmentioning

confidence: 99%

Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury

Yao

Lin

et al. 2017

Stem Cells

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“…However, most direct reprogramming methods have been generally optimized on mouse cells, which does not assure their efficacy on AHCFs (Chen et al, 2017). Indeed, AHCFs are known to be more resistant to cellular reprogramming than murine fibroblasts due to epigenetic barriers that hinder phenotypic changes (Talkhabi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

Paoletti

Divieto

Tarricone

et al. 2020

Front. Bioeng. Biotechnol.

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Modulation of microRNA expression holds the promise to achieve direct reprogramming of fibroblasts into cardiomyocyte-like cells as a new strategy for myocardial regeneration after ischemic heart disease. Previous reports have shown that murine fibroblasts can be directly reprogrammed into induced cardiomyocytes (iCMs) by transient transfection with four microRNA mimics (miR-1, 133, 208, and 499, termed "miRcombo"). Hence, study on the effect of miRcombo transfection on adult human cardiac fibroblasts (AHCFs) deserves attention in the perspective of a future clinical translation of the approach. In this brief report, we studied for the first time whether miRcombo transient transfection of AHCFs by non-viral vectors might trigger direct reprogramming of AHCFs into cardiomyocyte-like cells. Initially, efficient miRNA delivery to cells was demonstrated through the use of a commercially available transfection agent (DharmaFECT1). Transient transfection of AHCFs with miRcombo was found to upregulate early cardiac transcription factors after 7 days post-transfection and cardiomyocyte specific marker cTnT after 15 days post-transfection, and to downregulate the expression of fibroblast markers at 15 days post-transfection. The percentage of cTnT-positive cells after 15 days from miRcombo transfection was ∼11%, as evaluated by flow cytometry. Furthermore, a relevant percentage of miRcombo-transfected AHCFs (∼38%) displayed spontaneous calcium transients at 30 days post-transfection. Results evidenced the role of miRcombo transfection on triggering the trans differentiation of AHCFs into iCMs. Although further investigations are needed to achieve iCM maturation, early findings from this study pave the way toward new advanced therapies for human cardiac regeneration.

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“…Moreover, the effects of stoichiometry has been shown for Gata4, Tbx5 and Mef2c during cardiac direct reprogramming. 65 Moreover, it is interesting to express simultaneously the cardiac specific TFs with pluripotency inducing factors, or in a sequential manner, to avoid generation of any iPSC. This will increase the safety of partial reprogramming strategy, because it will direct the partially reprogrammed cells to inter to cardiac rout and eliminate possibility of iPSC generation.…”

Section: And Future Directionsmentioning

confidence: 99%

“…In addition to chemical‐based direct conversion, other approaches such as episomal‐based induction, protein transduction, mRNA transduction, and adenoviral‐based genes of interest overexpression can be studied for increasing the safety of partial reprogramming strategy in iCM/iCPC production. Moreover, the effects of stoichiometry has been shown for Gata4, Tbx5 and Mef2c during cardiac direct reprogramming . Moreover, it is interesting to express simultaneously the cardiac specific TFs with pluripotency inducing factors, or in a sequential manner, to avoid generation of any iPSC.…”

Section: Potential Applications and Future Directionsmentioning

confidence: 99%

“…Recent studies introduced a new and alchemy‐like strategy, known as trans differentiation, direct conversion or direct reprogramming, to produce desired cells such as CMs in vitro and in vivo . Here we use the word “direct cardiac conversion” to describe this cellular alchemy, and the produced cells using this strategy are called induced CMs (iCMs) or induced CPCs (iCPCs).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Partial reprogramming as a therapeutic approach for heart disease: A state‐of‐the‐art review

Talkhabi

2019

J of Cellular Biochemistry

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Heart disease such as myocardial infarction is the first cause of mortality in all countries. Today, cardiac cell‐based therapy using de novo produced cardiac cells is considered as a novel approach for cardiac regenerative medicine. Recently, an alchemy‐like approach, known as direct reprogramming or direct conversion, has been developed to directly convert somatic cells to cardiac cells in vitro and in vivo. This cellular alchemy is a short‐cut and safe strategy for generating autologous cardiac cells, and it can be accomplished through activating cardiogenesis‐ or pluripotency‐related factors in noncardiac cells. Importantly, pluripotency factors‐based direct cardiac conversion, known as partial reprogramming, is shorter and more efficient for cardiomyocyte generation in vitro. Today, this strategy is achievable for direct conversion of mouse and human somatic cells to cardiac lineage cells (cardiomyocytes and cardiac progenitor cells), using transgene free, chemical‐based approaches. Although, heart‐specific partial reprogramming seems to be challenging for in vivo conversion of cardiac fibroblasts to cardiac cells, but whole organism‐based in vivo partial reprogramming ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in mouse. Notably, cardiac cells produced using partial reprogramming strategy can be a useful platform for disease modeling, drug screening and cardiac cell‐based therapy, once the safety issues are overcome. Herein, we discuss about all progresses in de novo production of cardiac cells using partial reprogramming‐based direct conversion, as well as give an overview about the potential applications of this strategy in vivo and in vitro.

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Boosters and barriers for direct cardiac reprogramming

Cited by 10 publications

References 112 publications

Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury

Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury

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

Partial reprogramming as a therapeutic approach for heart disease: A state‐of‐the‐art review

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