Investigating the roles of fetal-specific genes in hematopoiesis

Abstract

Abstract Hematopoiesis, the process which generates blood cells, changes significantly during mammalian development. Fetal hematopoiesis primarily takes place in the fetal liver (FL), where hematopoietic stem cells (FL HSCs) are characterized by high self-renewal capacity and a distinctive program of multilineage differentiation. After birth, the main location of hematopoiesis is the bone marrow (BM), where stem cells (BM HSCs) are less proliferative and have a more restricted differentiation capacity. How exactly fetal hematopoiesis transitions to adult hematopoiesis and which cell-intrinsic properties or environmental factors aid this process have yet to be defined. This project aims to elucidate the cell-intrinsic mechanisms behind this transition. Studies show that FL and BM HSCs have distinct gene expression profiles, which may account for some of their phenotypic differences. Genes, such as LIN28B, which encodes an RNA binding protein, are highly expressed in the fetus, yet are absent in postnatal life. The re-expression of such fetal specific genes can confer fetal-like self-renewal and proliferation. Previous work in the Muljo lab demonstrated that LIN28B re-expression partially reprograms BM HSCs to undergo fetal-like lymphopoiesis, which is characterized by increased development of innate-like lymphocytes. I aim to fully reprogram adult BM HSCs to phenotypically resemble FL HSCs in their ability to generate cell types that develop early in life. FL HSCs, though clinically promising, are not readily available for therapeutic use. Reprogramming adult BM HSCs may be a suitable alternative that could improve current HSC transplantation procedures. This work is supported by the Intramural Research Program of NIAID, NIH. Intramural Research Program NIAID NIH