IL10 signalling in human vascular development: human vascular cell differentiation from induced-pluripotent stem cells
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PhD Thesis
Embargoed until: 2025-07-21
Reason: Author Request
Embargoed until: 2025-07-21
Reason: Author Request
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Cardiovascular disease (CVD) remains the primary cause of mortality worldwide. Existing treatment strategies, focusing on behavioral modification, pharmaceutical interventions, and surgical procedures, largely aim to slow the progression of these diseases rather than reverse their course. This approach falls short in fully addressing the complexities of these conditions. In this context, cardiovascular regenerative medicine emerges as a promising solution, particularly through the processes of vasculogenesis and angiogenesis. However, the intricate cellular and molecular mechanisms driving these regenerative processes are not completely understood. My research employed a chemically defined method to differentiate human-induced pluripotent stem cells (hiPSCs) into functional vascular cells, including smooth muscle cells (SMCs) and endothelial cells (ECs). A critical observation in my study was the significant and selective upregulation of interleukin 10 (IL10) during the mesodermal stage of vascular cell differentiation. Introducing IL10 into the mesoderm induction medium markedly improved the differentiation and functionality of both SMCs and ECs, whereas inhibiting IL10 resulted in reduced efficiency of differentiation. Our mechanistic studies revealed that IL10 facilitates vascular cell differentiation by activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway. As for functional studies, In vivo experiments using zebrafish larvae, where IL10 was knocked down using morpholino antisense oligonucleotides, revealed defective angiogenic sprouting and vascular development. Additionally, this PhD study also showed that IL10 not only promotes the development of blood vessel organoids but also significantly enhances vasculogenesis and angiogenesis. Further in vivo studies using a mouse model of hind limb ischemia (HLI) confirmed the role of IL10-induced hiPSC-derived ECs in promoting angiogenesis, vasculogenesis, and improving blood flow perfusion, shedding light on the therapeutic potential of these cells. In conclusion, this PhD study highlights the vital role of IL10 across multiple areas: vascular cell differentiation from hiPSCs, vascular development in zebrafish models, the creation of blood vessel organoids, and in enhancing angiogenesis under ischemic conditions. These insights offer novel perspectives in the realm of vascular cell differentiation, vasculogenesis, angiogenesis, and pave promising ways for stem cell therapy in the treatment of ischemic diseases. Keywords: Cardiovascular Disease; Vasculogenesis; Angiogenesis; Induced pluripotent stem cells (hiPSCs); Interleukin 10 (IL-10); Endothelial cell; Smooth muscle cell; Zebrafish; Blood vessel organoid; Hindlimb ischemia; Signal transducer and activator of transcription 3 (STAT3); Ischemic Disease Therapy.
Authors
Niu, KCollections
- Theses [4223]