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Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances

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Abstract

Irreversible myocardium infarction is one of the leading causes of cardiovascular disease (CVD) related death and its quantum is expected to grow in coming years. Pharmacological intervention has been at the forefront to ameliorate injury-related morbidity and mortality. However, its outcomes are highly skewed. As an alternative, stem cell-based tissue engineering/regenerative medicine has been explored quite extensively to regenerate the damaged myocardium. The therapeutic modality that has been most widely studied both preclinically and clinically is based on adult multipotent mesenchymal stem cells (MSC) delivered to the injured heart. However, there is debate over the mechanistic therapeutic role of MSC in generating functional beating cardiomyocytes. This review intends to emphasize the role and use of MSC in cardiac regenerative therapy (CRT). We have elucidated in detail, the various aspects related to the history and progress of MSC use in cardiac tissue engineering and its multiple strategies to drive cardiomyogenesis. We have further discussed with a focus on the various therapeutic mechanism uncovered in recent times that has a significant role in ameliorating heart-related problems. We reviewed recent and advanced technologies using MSC to develop/create tissue construct for use in cardiac regenerative therapy. Finally, we have provided the latest update on the usage of MSC in clinical trials and discussed the outcome of such studies in realizing the full potential of MSC use in clinical management of cardiac injury as a cellular therapy module.

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Fig. 1
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Fig. 3

reproduced with permission from Ref [38]). (B) Effect of HGF expressing MSC in cardio myogenesis and improvement in infarcted heart condition. (i) study design for cell loaded patch preparation (ii) 3D Printing of MSC loaded cells on a PCL framework. (iii) 3D printed patch (iv) Transplantation in a rat model of myocardium infarction, (v) isolated heart from patch transplanted in rats (reproduced with permission from Ref [39]), (C) Role of small molecule on improving the differentiation potential and efficiency of MSC into cardiomyocyte like cells. (i) Morphology of MSC when cultured with CHIR for 30 days, (ii) Positive staining of CHIR treated MSC-differentiated towards cardiomyocyte linage expressing cardiomyocyte-specific protein marker.; (ii) Enhanced gene expression of cardiomyocyte like gene from CHIR treated MSC as compared to untreated MSC. (reproduced with permission from Ref [40]); (D) Cardiomyogenic differentiation of MSC on cardiac fibroblast derived extracellular matrix (cardiogel). (i) and (ii) differentiation on tissue culture plates without and with 5Aza treatment in the absence of cardiogel respectively, (iii) and (iv) cardiomyocyte like cells derivation from MSC when cultured on cardio gel without and with 5 Aza treatment respectively (reproduced with permission from Ref [41])

Fig. 4

reproduced with permission from Ref [69]); (B) Differentiation of MSC into cardiomyocytes like cells when cultured on nanopatterned substrate. (i) nanopattern plates (ii) shapes and morphology of nanopattern used for MSC culture and differentiation, (iii) morphology of MSC upon differentiation to cardiomyocytes like cells due to nontopographical cues. (reproduced with permission from Ref [70]); (C) Effect of mechanical cyclical stretching on induction of cardio myogenesis in MSC. (i) Set up used for subjecting cultured MSC on silicon to cyclical stretching (ii) diagrammatic representation of the setup, (iii) MSC undergoing change in morphology and alignment and staining possible for the cardiomyocytes marker, (iv) Increased cardiomyocytes specific gene expression of MSC under cyclical stretching (v) cells showing positive staining for cardiomyocytes specific marker (reproduced with permission from Ref [71]); (D) Effect of electrical stimulation on cardiomyogenic induction of MSC. MSC cultured on carbon nanotube-poly Lactic acid nanofiber showed positive staining for cardiomyocytes specific protein marker (reproduced with permission from Ref [22])

Fig. 5
Fig. 6

reproduced with permission from Ref [93]). (B). Autophagy induced by MSC-derived exosomes decreases CM apoptosis. B(i) Autophagy protein detection. B(ii) CM apoptosis measured using TUNEL assay. B(iii) MI size detected by staining. (reproduced with permission from Ref [94]). (C). Effect of integrin-linked kinase (ILK)-MSC conditioned medium on MI size and fibrosis. C(i) Infarct size in different experiment groups with Masson Trichrome staining. C(ii) Quantification of stained myocardial area (reproduced with permission from Ref [95]). (D). MSCs stimulate endogenous cardiac stem cells. D(i) Contribution of CM precursors following exogenous administration of MSCs. D(ii) 2 weeks the number of C-kit + cells co-expressing GATA-4 D(iii-iv) Chimeric myocardium contains CM (open arrow), MSCs (arrowheads, inset) and cardiac precursors of MSCs origin (arrow), coupled by connexin-43. D(v) Cluster of c-kit + CSCs in an MSCs-treated heart. D (vi) c-kit + cells found in non-MSC treated animals (reproduced with permission from ref [96]). (E). MSC-conditioned media suppresses ROS generation under hypoxic conditions. E(i) Fluorescence images corresponding to ROS suppression. (reproduced with permission from Ref [97]). (F). miR-486-5p from exosomes derived from MSC inhibit apoptosis of CM. F(i) Cell viability ratio of H9C2 cells treated with different mi-BMSC-exosomes. F(ii-iii) Flow cytometry analysis. (reproduced with permission from Ref [98]). (G). Exosomes derived from MSCs promote angiogenesis. G(i) Representative images of tube-like structures and quantitation of the total tube length in control and exosome treated groups. G(ii) Gross look of matrigel plugs. G(iii) Haemoglobin content. G(iv) CD31 staining and quantification of the CD31-positive cells (reproduced with permission from Ref [99])

Fig. 7
Fig. 8

reproduced with permission from Ref [194]). (B). Microfluidic device (MD) for directional migration of MSCs. B(i) The MD set up. B(ii) MSC extravasation and migration in MD. B(iii) Endothelial monolayers and MSC migration due to SDF-1α gradient. B(iv) MSC extravasation (reproduced with permission from Ref [152]). (C). Cell sheet technology. C(i) The thermoresponsive culture surface supports cell adhesion and detachment. C(ii) Magneto-fluorescent stem cell sheet. C(iii) 3D reconstitution of cell sheet(reproduced with permission from Ref [198]). (D). Dual approach improves cardiac function following MI. D(i) Cardiac function in rats receiving cardiomyocytes derived from human iPSC with human MSC cell-loaded patch. D(ii) Images of stained capillaries 8 weeks after MI. D (iii) Representative images from the experimental groups showing cardiac fibrosis after staining with Masson’s trichrome 8 weeks after MI (reproduced with permission from Ref [199]). (E). Electrospinning as a tool for hMSC application. E(i) Nanofiber scaffolds based on polyvinyl alcohol, chitosan and carbon nanotubes for differentiation of hMSC (reproduced with permission from Ref [200])

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Data Availability

Data that support the findings of this study are available in the manuscript.

Abbreviations

MSCs:

Mesenchymal Stem Cells

hMSCs:

human Mesenchymal Stem Cells

BM MSC:

Bone Marrow Mesenchymal Stem Cells

hUC-MSCs:

Human Umbilical Cord Mesenchymal Stem Cells

CLC:

Cardiomyocyte Like Cells

CPC:

Cardiac Progenitor Cells

CSCs:

Cardiac Stem Cells

hiPSC:

Human induced Pluripotent Stem Cells

CRT:

Cardiac Regenerative Therapy

CVD:

Cardiovascular Disease

BMP:

Bone Morphogenetic Protein

VEGF:

Vascular Endothelial Growth Factor

TGF-β1:

Transforming Growth Factor Beta1

FGF:

Fibroblast Growth Factor

PDGF:

Platelet Derived Growth Factor

HGF:

Hepatocytes Growth Factor

GSK-3β:

Glycogen Synthase 3 beta

MHC:

Major Histocompatibility Complex

5Aza:

5 Azacytidine

ECM:

Extracellular Matrix

miRNA:

Micro RNA

HDAC:

Histone Deacetylase Inhibitor

GATA4:

GATA-binding factor 4

Nkx2.5:

Homeobox Protein Nkx-2.5

CMHC:

Cardiac Myosin Heavy Chain

cTnI:

Cardiac Troponin

C43:

Connexin43

EVs:

Extracellular Vesicles

CNT:

Carbon Nanotube

3D Printing:

3-Dimensional Printing

CMC:

Cardiac Mesenchymal Cells

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Acknowledgements

SG would like to acknowledge Indian Council of Medical Research (ICMR) for fellowship (3/1/3/JRF-2015/HRD-LS/90/40282/91). AS would like to acknowledge Indian Institute of Technology (IIT) Madras for HTRA fellowship. The authors would also like to acknowledge the support by Department of Biotechnology (DBT), India for their funding and support (BT/PR8587/MED/31/236/2013).

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  1. Santosh Gupta and Akriti Sharma has contributed equally as the first author.

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  1. Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India

    Akriti Sharma, Santosh Gupta, S Archana & Rama Shanker Verma

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Conceptualization: [Santosh Gupta], [Akriti Sharma], [Rama Shanker Verma]; Methodology: [Akriti Sharma], [Santosh Gupta], [Rama Shanker Verma]; Formal analysis and investigation: [Santosh Gupta], [Akriti Sharma]; Writing—original draft preparation: [Akriti Sharma], [Santosh Gupta], [Archana S], [Rama; Writing—review and editing: [Santosh Gupta], [Akriti Sharma], [Archana S], [Rama Shanker Verma]; Funding acquisition: [Not Applicable]; Resources: [Not Applicable]; Supervision: [Rama Shanker Verma].

[Santosh Gupta] and [Akriti Sharma] has contributed equally as the first author. Their names can be interchangeably used in the first position.

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Correspondence to Rama Shanker Verma.

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Sharma, A., Gupta, S., Archana, S. et al. Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances. Stem Cell Rev and Rep 18, 1546–1602 (2022). https://doi.org/10.1007/s12015-021-10314-8

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