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Jyotsna _CSU_Dissertation-OHIOLINK.pdf (7.98 MB)

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Engineering the Micro-Environment Niche of Human Bone Marrow-Derived Mesenchymal Stem Cells for Enhanced Cardiac Tissue Regeneration

Joshi, Jyotsna
http://rave.ohiolink.edu/etdc/view?acc_num=csu1543925924170549

Abstract Details

2018, Doctor of Engineering, Cleveland State University, Washkewicz College of Engineering.
The intrinsic repair mechanism of human heart is not sufficient to overcome the impact placed by adverse pathological conditions, such as myocardial infarction (MI). Current clinical approaches have played significant role in reducing the mortality rate; however, these approaches do not replace the lost cells and tissues of the myocardium. Human bone marrow-derived mesenchymal stem cells (BM-MSCs) are gaining attention in cardiac therapy due to their ability to differentiate into cardiomyocyte like cells and release a wide repertoire of paracrine factors. However, clinical trials of longer duration have shown mixed results in improving cardiac functions. In addition, in-depth studies on the secretome profile of MSCs/ differentiated MSCs and optimal approaches to modulate their outcomes are still lacking. Hence, in the first project of this study, we investigated the role of cell-cell interactions (MSC spheroids), cell-matrix interactions (collagen concentration, topography) and cell-signaling cues [5-azacytidine (aza)] on the cardiac differentiation of BM-MSCs. We found that collagen hydrogel (2 mg/ml), in the presence of 10 µM of aza, offered higher cell survival and caused time-dependent cardiomyogenic evolution of MSC spheroids. We also identified that canonical Wnt/ß-catenin signaling pathway primarily mediated the observed benefits of aza on cardiac differentiation of MSC spheroids. In the second project, we quantified the secretome profile and matrix synthesis by collagen gel-laden BM-MSC spheroids, under optimized culture conditions from the first project, and extended our investigation to MSC spheroids within human fibroblasts-derived collagen. Human collagen promoted higher matrix synthesis over time but severely impacted cell proliferation. The release of inflammatory cytokines was drastically reduced with spheroid formation and collagen cultures, specifically within human collagen. In the last project, we examined the influence of adult human cardiomyocytes cocultures on the survival, differentiation, secretome release and matrix synthesis by the MSC spheroids within 3D collagen gels, under healthy and transforming growth factor-alpha (TNF-α)-stimulated conditions. We noted higher cardiomyocyte differentiation from MSCs within control cocultures and higher synthesis of matrix components and reduced levels of inflammatory cytokines within TNF-α-stimulated cultures. Such collagen gel-laden MSC spheroids show potential to replace the lost cells and tissues in the infarct region following MI.
Chandra Kothapalli (Committee Chair)
Moo-Yeal Lee (Committee Member)
Nolan B. Holland (Committee Member)
Mekki Bayachou (Committee Member)
Anand Ramamurthi (Committee Member)
257 p.
Biomedical Engineering
Myocardial infarction; Human bone marrow-derived mesenchymal stem cells; MSC spheroids; 5-azacytidine; Collagen hydrogels; Collagen nanofibers; Wnt signaling; MSC paracrine signaling; TNF-alpha; Human cardiomyocytes; Cocultures of MSC and cardiomyocytes

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Citations

  • Joshi, J. (2018). Engineering the Micro-Environment Niche of Human Bone Marrow-Derived Mesenchymal Stem Cells for Enhanced Cardiac Tissue Regeneration [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1543925924170549

    APA Style (7th edition)

  • Joshi, Jyotsna. Engineering the Micro-Environment Niche of Human Bone Marrow-Derived Mesenchymal Stem Cells for Enhanced Cardiac Tissue Regeneration. 2018. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1543925924170549.

    MLA Style (8th edition)

  • Joshi, Jyotsna. "Engineering the Micro-Environment Niche of Human Bone Marrow-Derived Mesenchymal Stem Cells for Enhanced Cardiac Tissue Regeneration." Doctoral dissertation, Cleveland State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1543925924170549

    Chicago Manual of Style (17th edition)

csu1543925924170549
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© 2018, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.