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Endothelial regulation in cell fate specification during embryonic development of the lung and the hematopoietic system

University of British Columbia

Embryonic development is a highly coordinated process during which cells undergo regulated division, differentiation, and migration to ultimately shape specialized tissues that perform particular functions. Throughout this course, cell fate is driven by intrinsic cell decisions in response to microenvironmental cues from their surroundings and understanding what governs these processes is at the core of developmental biology. Aberrant expression of essential developmental genes typically elicits apparent embryonic defects due to disruption of normal developmental processes. Thus, investigation of the resulting phenotype in animal models provides valuable insights into their role and overall biological pathways driving organogenesis. The work presented in this dissertation investigates the role of such developmental genes and uncovers significant signaling interactions involving endothelial cells to promote cell specification and maturation of non-vascular cells. First, this study explores the contribution of Sash1 during organogenesis. Examination of Sash1-knockout mouse embryos revealed cell non-autonomous functions in regulating both prenatal lung development and embryonic hematopoiesis. On one hand, endothelial Sash1 signaling in the lung promoted nitric oxide production which plays a critical role in the maturation of alveolar epithelial cells prior to birth. On the other hand, Sash1 expression in non-endothelial cells contributed to the emergence of hematopoietic stem and progenitor cells during the endothelial-to-hematopoietic transition (EHT) in the early embryo. Our findings suggest that Sash1 in the microenvironment impacts the progression of specified hemogenic endothelial cells into hematopoietic clusters and the work presented in chapter 4 identifies multiple candidate cell types as the origin of Sash1 signaling. In addition, early specification of a hemogenic endothelium distinct from its arterial counterpart is a critical event at the origin of EHT. Therefore, the last part of the study explored factors influencing endothelial cell fate and provided evidences to support a role for the developmental gene Meis1 in driving early hematopoietic commitment of the endothelium while showing that loss of its expression significantly impairs EHT. Altogether, the data presented in this dissertation highlights critical functions for Sash1 and Meis1 in embryogenesis and showcases examples of communication from, to, and within endothelial cells to influence cell fate in organogenesis.

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2021-04-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/77700

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/