A Novel Variant of ADAMTS13 Regulates Angiogenic Markers in Human Stem Cells under Nutrient Stress Condition

Dutta Gupta, Srishti (2025) A Novel Variant of ADAMTS13 Regulates Angiogenic Markers in Human Stem Cells under Nutrient Stress Condition. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Srishti Dutta Gupta (19RS080)) 19RS080.pdf - Submitted Version Restricted to Repository staff only Download (24MB)

Abstract

Mesenchymal stem cells (MSCs) secrete many trophic factors, known to promote angiogenesis and neovascularization. However, post-transplantation, MSCs often encounter adverse microenvironmental conditions like nutrient-deprivation, hypoxia or an inflammatory milieu, which hamper their efficacy. Our study identified a novel factor involved in regulating angiogenic markers in human umbilical cord-derived Wharton’s Jelly MSCs (WJ-MSCs) under nutrient stress condition. ADAMTS13, the von Willebrand factor (vWF) cleaving protease, was found to be upregulated under nutrient stress. Correspondingly, potent pro-angiogenic markers like VEGF, PDGF, IL-6 and TNF-α were also upregulated. Moreover, the p38 and JNK signaling pathways were identified as negative and positive regulators of ADAMTS13 expression, respectively, in nutrient-stressed WJ-MSCs. siRNA-mediated knockdown of ADAMTS13 in nutrient-stressed WJ-MSCs led to a significant reversal in the expression of the angiogenic markers, suggesting that ADAMTS13 was playing a role in regulating them. Our study also demonstrated that ADAMTS13 acted via the EphrinB2/EphB4 tyrosine kinase axis, followed by ERK signaling, to modulate the expression of these downstream angiogenic markers. Furthermore, we identified an alternatively spliced variant of ADAMTS13 generated by exon skipping in MSCs. Functionally, this variant partially retained the vWF cleavage activity. Overall, our findings outline the existence of a novel variant of ADAMTS13 in MSCs, which acts as a critical factor in controlling the expression of angiogenic markers under nutrient stress. Additionally, we established a distinct role of the extracellular matrix glycoprotein, vitronectin (VTN), in regulating the adhesion and migration of placenta-derived MSCs (PL-MSCs) under nutrient stress. We demonstrated that VTN, induced under nutrient stress, regulated the assembly and maturation of stress fibers and focal adhesions, leading to increased adhesion and reduced migration of the cells and acted as an upstream stimulator of myosin light chain phosphorylation. Hence, this part of the study defined a unique role of VTN as a modulator of migration in nutrient-stressed PL-MSCs.

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