Recent Progress in Stem Cell Modification for Cardiac Regeneration

Lemcke, Heiko; Voronina, Natalia; Steinhoff, Gustav; Dávid, Róbert

doi:10.1155/2018/1909346

Cited by 65 publications

(66 citation statements)

References 247 publications

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“…The mounting stress on aging further induces RCS leading to a hyper-oxidative condition in the infarcted regions of the myocardium (16, 17). Currently, transplantation of iPS-derived cardiomyocytes (iPS-CMs) into the infarcted areas results in their death due to necrosis and/or apoptosis, thereby reducing their survival and poor implantation/repair (18-20). Therefore, understanding the redox-dependent mechanisms that are vital for augmented survival and engraftment of iPS-CMs is essential.…”

Section: Introductionmentioning

confidence: 99%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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Background: Reprogramming of somatic cells into pluripotent stem cells (iPSC) and subsequent differentiation into iPSC-derived cardiomyocytes (iCM) seems to be a promising strategy for cardiac regenerative therapy. However, recent failure or poor outcomes in cardiac cell therapy warrants further investigation focusing on the infarction/wound environment (site of healing) to improve the cardiac regenerative medicine. Here, using next generation sequencing (NGS), we analyzed the global transcriptome to discover the unidentified genes/pathways that are crucial for cell survival, cytoprotection and mitochondrial dynamics during the differentiation of iPSC into iCM.Methods: High throughput NGS was performed RNA from human iPSCs and iCMs (n=3/group) and analyzed the global changes in the transcriptome during differentiation. Furthermore, Ingenuity Pathway Analysis (IPA) and Gene Ontology (GO) for biological process were performed to understand the transcriptional networks that are involved during iCM differentiation. RNA-seq data were further validated by qRT-PCR analyses. Results:Global transcriptome analysis revealed that ~9,290 genes (log 2 FC >2) were significantly altered in human iCMs compared to the parent iPSCs, in which 4,784 transcripts were substantially upregulated and 4,506 transcripts were down-regulated during differentiation.GO enrichment and IPA analyses revealed the top 10 regulatory networks (i.e. hierarchical order) involved in differentiation of iCMs including cardiomyocyte remodeling, integrin-linked kinase signaling, Rho family of GTPases, etc. Surprisingly, none of the top 10 pathways listed the genes liable for redox signaling networks that are crucial for the basal cellular redox homeostasis, Nrf2-dependent antioxidant defense, mitochondrial functions and cell survival. Our deeper and unbiased analysis of this data revealed that the genes involved in above canonical signaling pathways are found in the middle of the inverted vertical cone. Of note, although these pathways are significantly altered during the differentiation (of iPS into cardiomyocytes), a majority of them are ranked low in the hierarchical list (>150). Validation of the randomly selected genes representing various pathways real-time qPCR confirmed the global transcriptome changes observed in NGS. Conclusion:We highlight the significance of Nrf2-redox and mitochondrial transcriptome during differentiation of iPSC into iCMs. Thus, targeting the redox signaling mechanisms in iCMs may enhance their efficiency for cell therapy and improved myocardial repair.180 genes were detected out of 230 genes known to constitute this pathway, whereas 58 genes were increased and 56 genes were decreased. From this list, the top 15 up and down-regulated genes were used to generate the heat-maps. A substantial list of genes were downregulated during cardiomyocyte differentiation including, MGST1, GSTM5, PRKCQ, PRKCB and PIK3R, while PIK3R5ACTA2, GSTM3, FMO1, ACTC1 and GSTA3 were increased during cardiomyocyte differentiation. RNA-seq data was valid...

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Section: Introductionmentioning

confidence: 99%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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“…These cytokines not only promote vascular regeneration, but also protect myocardium in hypoxia [35]. Our results indicate that CD73 + ADMSCs, ADMSCs and CD73 -ADMSCs can significantly improve cardiac function of rats with myocardial infarction, but that CD73 + ADMSCs transplantation appears to be more effective.…”

Section: Discussionmentioning

confidence: 61%

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

Li¹,

Hou

et al. 2020

Preprint

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Background: Cardiovascular disease is the leading cause of death in developed and developing countries. The lack of effective regenerative therapies in the treatment of ischemia‐related diseases requires new therapies to improve clinical outcomes. Thus, MSCs have become a focus in stem cell treatment of myocardial injury. At present, most studies use mixed MSCs in vivo and in vitro. A promising therapeutic strategy for myocardial injury should be using the dominant subgroup with essential biological characteristics. The aim of this study was to utilize the dominant CD73 + subgroup of adipose derived mesenchymal stem cells (ADMSCs) for the therapy of myocardial infarction (MI). Methods: Adult mix gender SD rats, with a body weight of 230±18g, were randomly divided into sham operation group (SHAM), MI group (MI), mixed ADMSCs transplantation group (MI+ADMSCs), CD73 + ADMSCs transplantation group (MI+CD73 + ADMSCs) and CD73 - ADMSCs transplantation group (MI+CD73 - ADMSCs). CD73 + ADMSCs were isolated using flow cytometry and then cultured. Overexpression and inhibition of CD73 gene of ADMSCs using lentiviral vectors. Differential genes analysis of CD73 + ADMSCs vs. CD73 - ADMSCs were based on GO analysis. The effect of CD73 on the secretion of cytokines was measured by ELISA. Myocardial infarction model and cell transplantation model were replicated. Detection of cardiac function of rats by color doppler ultrasound after operation. The expression of VEGF and factor VIII and neovascularization were detected by immunohistochemistry and Western Blotting. Results: We demonstrated that, compared to mixed ADMSCs and CD73 - ADMSCs, CD73 + ADMSCs were more effective in the promotion function of cardiac recovery in a rat model of MI. CD73 + subset promoted vascular regeneration in myocardial injured regions. We also showed that expression of CD73 promoted secretion of VEGF, HIF-1α and HGF factors in ADMSCs. CD73 + ADMSCs displayed significantly different transcription profile compared to CD73 - ADMSCs, in particular, concerning VEGF pathways. Conclusions: Overall, CD73 + ADMSCs were the dominant subgroup and the presence of the surface marker CD73 can be used as a MSCs cell quality control for treatment of myocardial injury by angiogenesis.

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“…Ongoing researches on preconditioning and genetic manipulations of MSCs are needed to enhance angiocrine capacity governed by growth factors, microvesicles, microRNAs, long noncoding RNAs (lncRNAs), etc. [128,129]. Finding the route of cell delivery, the optimum dose, the excellent cell source, and transplantation time are factors that still require to be addressed so as to achieve the aim of comprehensive cardiac regeneration.…”

Section: The Application Of Mscs and Secretome In Ischemic Cardiac DImentioning

confidence: 99%

The Angiogenic Paracrine Potential of Mesenchymal Stem Cells

Rezaie¹,

Heidarzadeh²,

Hassanpour³

et al. 2020

Update on Mesenchymal and Induced Pluripotent Stem Cells

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Tissue engineering and regenerative medicine are branches of biomedical sciences that facilitate the use of cells and biocompatible scaffolds in favor of tissue restoration. In this regard, restoration and maintenance of angiogenesis and blood supplementation could be an effective strategy for injured tissue removal, accelerating healing rate, and successful transplantation of cells and scaffolds into target sites. It has been elucidated that mesenchymal stem cells have the potency to promote angiogenesis via paracrine activity and trans-differentiation into the endothelial lineage. In this chapter, we highlighted the paracrine property of mesenchymal stem cells to modulate angiogenesis in the target tissues.

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Recent Progress in Stem Cell Modification for Cardiac Regeneration

Cited by 65 publications

References 247 publications

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

The Angiogenic Paracrine Potential of Mesenchymal Stem Cells

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