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Role of Inflammatory Niche and Adult Cardiomyocyte Coculture on Differentiation, Matrix Synthesis, and Secretome Release by Human Bone Marrow Mesenchymal Stem Cells

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Abstract

Myocardial infarction (MI) causes cardiomyocyte death, provokes innate immune response, and initiates tissue remodeling. The intrinsic healing process is insufficient to replace the lost cells, or regenerate and restore the functional features of the native myocardium. Autologous bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation is being explored to offer therapeutic potential after MI. Here, we cultured human BM-MSC spheroids in three-dimensional collagenous gels for 28 days under exposure to tumor necrosis factor-alpha (+ TNFα), and coculture with adult human cardiomyocytes, or with conditioned media (CM) pooled from TNFα-stimulated adult cardiomyocytes. MSC differentiation marker (CD90, GATA4, cTnI, cTnT, Cx43, MHC, α-actin) expression, matrix protein (elastin, hyaluonic acid, sulfated glycosaminoglycans, laminin, fibrillin, nitric oxide synthase) synthesis, and secretome (cytokines, chemokines, growth factors) release at days 12 and 28 were assessed. MSC density decreased with duration in all culture conditions, except in controls. GATA4 expression was higher in cocultures but lower in + TNFα cultures. Synthesis and deposition of various extracellular matrix proteins and lysyl oxidase within MSC cultures, as well as secretome composition, were strongly dependent on the culture condition and duration. Results suggest that TNFα-induced inflammation suppresses BM-MSC survival and differentiation into mature cardiomyocytes by day 28, while promoting matrix protein synthesis and cytokine release conducive to MI remodeling. These findings could have implications in developing tissue engienering and cell transplantation strategies targeting MI, as well as to develop therapuetics to target inflammation-induced matrix remodeling post-MI.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

CK expresses his gratitude to the CSU Office of Research funds, and JJ thanks the financial support from the Cellular and Molecular Medicine Specialization Fellowship and Dissertation Research Award from CSU.

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  1. Jyotsna Joshi

    Present address: Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, 85259, USA

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  1. Department of Chemical and Biomedical Engineering, Cleveland State University, 2121 Euclid Avenue, FH 460, Cleveland, OH, 44115, USA

    Jyotsna Joshi & Chandrasekhar R. Kothapalli

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  1. Jyotsna Joshi
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  2. Chandrasekhar R. Kothapalli
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JJ: experiments, data analysis, methodology, writing original draft, review and editing of final draft. CK: conceptualization, data analysis, funding acquisition, methodology, project administration, resources, writing original draft, review and editing of final draft.

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Correspondence to Chandrasekhar R. Kothapalli.

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Joshi, J., Kothapalli, C.R. Role of Inflammatory Niche and Adult Cardiomyocyte Coculture on Differentiation, Matrix Synthesis, and Secretome Release by Human Bone Marrow Mesenchymal Stem Cells. Appl Biochem Biotechnol 194, 1938–1954 (2022). https://doi.org/10.1007/s12010-022-03803-0

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