Early Career Fellowship research summary

In embryos as well as adult tissues stem cells are proliferated and maintained in niches. The niches provide microenvironment that nurtures stem cells and also prevent their excessive proliferation. Morphogens such as Bone morphogenetic proteins, Wnt, Notch, and Hedgehog are part of the niche and play a significant role in maintenance of stem cells.

In healthy individuals billions of new blood cells are replenished daily from haematopoietic stem cells. Haematopoietic stem cells residing in the bone marrow of adults or in developing embryos have the unique ability to replicate and differentiate in to all different mature blood cells. Self renewal of the stem cell pool is one of the critical requirements to ensure continuous replenishment of new blood cells. Morphogens, including Hedgehog family of proteins, involved in patterning the developing embryos have also emerged at major players in maintenance and proliferation of several stem cells including haematopoietic stem cells. Unlike other secretory morphogens, Hedgehog and Wnt family members are known to be tethered to the cell surface via their lipid modifications; yet they are secreted for their function in vivo. The molecular mechanism of secretion of such membrane anchored morphogens remains highly controversial and poorly resolved especially in vertebrates. Using genetic perturbations and pharmacological inhibitors as tools, I am interested in exploring the mechanisms of secretion of vertebrate Hedgehog family of proteins by embryoid bodies derived from mouse and human embryonic stem cells. Haematopoiesis in mice will be monitored to explore the in vivo consequences of selective perturbations.