Dataset Information

Engineering stem cell cardiac patch with microvascular features representative of native myocardium.

ABSTRACT: The natural myocardium is a highly aligned tissue with an oriented vasculature. Its characteristic cellular as well as nanoscale extracellular matrix (ECM) organization along with an oriented vascular network ensures appropriate blood supply and functional performance. Although significant efforts have been made to develop anisotropic cardiac structure, currently neither an ideal biomaterial nor an effective vascularization strategy to engineer oriented and high-density capillary-like microvessels has been achieved for clinical cardiovascular therapies. A naturally derived oriented ECM nanofibrous scaffold mimics the physiological structure and components of tissue ECM and guides neovascular network formation. The objective of this study was to create an oriented and dense microvessel network with physiological myocardial microvascular features.

Methods

Highly aligned decellularized human dermal fibroblast sheets were used as ECM scaffold to regulate physiological alignment of microvascular networks by co-culturing human mesenchymal stem cells (hMSCs) and endothelial cells (ECs). The influence of topographical features on hMSC and EC interaction was investigated to understand underlying mechanisms of neovasculature formation.

Results

Results demonstrate that the ECM topography can be translated to ECs via CD166 tracks and significantly improved hMSC-EC crosstalk and vascular network formation. The aligned ECM nanofibers enhanced structure, length, and density of microvascular networks compared to randomly organized nanofibrous ECM. Moreover, hMSC-EC co-culture promoted secretion of pro-angiogenic growth factors and matrix remodeling via metalloprotease-2 (MMP-2) activation, which resulted in highly dense vascular network formation with intercapillary distance (20 ?m) similar to the native myocardium.

Conclusion

HMSC-EC co-culture on the highly aligned ECM generates physiologically oriented and dense microvascular network, which holds great potential for cardiac tissue engineering.

SUBMITTER: Qian Z

PROVIDER: S-EPMC6531308 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Engineering stem cell cardiac patch with microvascular features representative of native myocardium.

Qian Zichen Z Sharma Dhavan D Jia Wenkai W Radke Daniel D Kamp Timothy T Zhao Feng F

Theranostics 20190409 8

The natural myocardium is a highly aligned tissue with an oriented vasculature. Its characteristic cellular as well as nanoscale extracellular matrix (ECM) organization along with an oriented vascular network ensures appropriate blood supply and functional performance. Although significant efforts have been made to develop anisotropic cardiac structure, currently neither an ideal biomaterial nor an effective vascularization strategy to engineer oriented and high-density capillary-like microvesse ...[more]

PMID: 31149034

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Project description:The myocardium is a diverse environment, requiring coordination between a variety of specialised cell types. Biochemical crosstalk between cardiomyocytes (CM) and microvascular endothelial cells (MVEC) is essential to maintain contractility and healthy tissue homeostasis. Yet, as myocytes beat, heterocellular communication occurs also through constantly fluctuating biomechanical stimuli, namely (1) compressive and tensile forces generated directly by the beating myocardium, and (2) pulsatile shear stress caused by intra-microvascular flow. Despite endothelial cells (EC) being highly mechanosensitive, the role of biomechanical stimuli from beating CM as a regulatory mode of myocardial-microvascular crosstalk is relatively unexplored. Given that cardiac biomechanics are dramatically altered during disease, and disruption of myocardial-microvascular communication is a known driver of pathological remodelling, understanding the biomechanical context necessary for healthy myocardial-microvascular interaction is of high importance. The current gap in understanding can largely be attributed to technical limitations associated with reproducing dynamic physiological biomechanics in multicellular in vitro platforms, coupled with limited in vitro viability of primary cardiac tissue. However, differentiation of CM from human pluripotent stem cells (hPSC) has provided an unlimited source of human myocytes suitable for designing in vitro models. This technology is now converging with the diverse field of tissue engineering, which utilises in vitro techniques designed to enhance physiological relevance, such as biomimetic extracellular matrix (ECM) as 3D scaffolds, microfluidic perfusion of vascularised networks, and complex multicellular architectures generated via 3D bioprinting. These strategies are now allowing researchers to design in vitro platforms which emulate the cell composition, architectures, and biomechanics specific to the myocardial-microvascular microenvironment. Inclusion of physiological multicellularity and biomechanics may also induce a more mature phenotype in stem cell-derived CM, further enhancing their value. This review aims to highlight the importance of biomechanical stimuli as determinants of CM-EC crosstalk in cardiac health and disease, and to explore emerging tissue engineering and hPSC technologies which can recapitulate physiological dynamics to enhance the value of in vitro cardiac experimentation.

Project description:Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear.To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model.Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups.This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.

Dataset Information

Engineering stem cell cardiac patch with microvascular features representative of native myocardium.

Methods

Results

Conclusion

Publications

Engineering stem cell cardiac patch with microvascular features representative of native myocardium.

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