Role of outside-in integrin signaling in hematopoietic development of mouse embryo

The fetal liver (FL) is a prominent transient site for hematopoietic development in mammals. During hematopoietic ontogeny, immature HSCs migrate from primitive sites to the FL. The FL niche supports concomitant proliferation and maturation of nascent HSCs. The niche, composed of cells and regulatory factors, maintains the overall functionality of stem cells. Integrins, a class of adhesion receptors, located on HSC surface help transduce extrinsic signals from the niche, facilitating stem cell regulation. Itgav-b3, along with its ligand Postn, was shown to maintain HSC quiescence in the bone marrow (BM) (Khurana S. et al, 2016). RNA seq and flow cytometry data showed the presence of Itgav-b3 on FL HSCs as well. We questioned the role of Postn-Itgav axis in a site where HSC proliferation is the key feature. We found that disruption of Postn-Itgav axis in the FL led to further proliferation of FL HSCs. Interestingly, such proliferative events gave rise to functionally viable stem cells, unlike in the BM (Khurana S. et al, 2016). Further investigation showed that FL LSKs from induced proliferation culture as well as highly proliferative Postn-/- FL LSKs exhibited heightened DNA damage response (DDR), as opposed to wildtype. We propose that higher DDR might be the underlying reason for better tolerance of proliferative stress, thereby reflecting a developmental stage-dependent effect (Biswas A. et al, 2020). HSC proliferation in the FL gives rise to functionally potent stem cells, making the FL HSC niche a remarkable site for investigation. A composite understanding of the FL HSC microenvironment remains largely elusive. Following up on our studies on FL hematopoiesis, we made efforts to understand the composition of the HSC micro-niche within this tissue. Extensive 3D image analysis helped us draw a preliminary unbiased cellular architecture of the FL HSC niche.