Optimising the myocardial homing and therapeutic efficacy of mesenchymal stem cells using 3D culture and specific subpopulations of bone marrow-derived cells

Bumroongthai, Kobkaew (2021). Optimising the myocardial homing and therapeutic efficacy of mesenchymal stem cells using 3D culture and specific subpopulations of bone marrow-derived cells. University of Birmingham. Ph.D.

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Abstract

Myocardial infarction (MI) results from ischemia and reperfusion (IR) injury and is the significant cause of death worldwide. Bone marrow mesenchymal stem cell (BM-MSC) transplantation has been identified as having the most potential to treat a broad range of diseases due to their unique ability to evade the host immune system. However, clinical success is limited due to poor homing and survival of MSCs in the injured heart. There is still no consensus on which stem cell population confers the most therapeutic capacity to treat heart disease. Furthermore, the cellular targets of MSC actions and the mechanisms explaining their therapeutic effects are still not fully understood. This current study used two subpopulations of human BM-MSCs (hBM-MSCs) originally derived from the same bone marrow site called hBM-MSCs Y201 and hBM-MSCs Y202. The hBM-MSCs Y201 were a highly tri-lineage differentiating, CD317neg MSC subset, with the expression of genes consistent with perivascular interactions in the BM. hBM-MSCs Y202 were a subpopulation that included non-differentiating CD317pos BM resident MSCs, which did not express genes associated with vascular interactions. We are the first group to image in real-time the kinetics of MSC recruitment and their impact on microvascular events at a cellular level in a mouse beating injured heart model. This current study provides novel pieces of evidence to show that subpopulations of hBM-MSCs possessed different retention potential to mouse beating heart and anti-inflammatory capacities to ameliorate myocardial IR injury. 3D culture technique improved hBM-MSCs Y201 vasculoprotective benefits in reducing the thromboinflammatory response within the coronary microcirculation. hBM-MSCs derived from 3D spheroid were much smaller, which may reduce their pulmonary microvascular entrapment, leading to increased trafficking through the heart, which enhanced their therapeutic effect. The mechanism of vasculoprotective benefits of 3D cultured hBM-MSCs Y201 may have been accomplished by lowering coronary endothelial cells oxidative stress and reducing the levels of plasma pro-inflammatory cytokines. Combination therapy of 3D cultured hBM-MSCs Y201 with unfractionated heparin reduced neutrophils and platelets' recruitment within the coronary microcirculation following IR injury.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):