Forming the hematopoietic stem cell niche from pluripotent stem cells
- Author(s): Chin, Chee Jia
- Advisor(s): Crooks, Gay M
- et al.
Hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and contribute to multi-lineage differentiation, critical functions that ensure homeostatic production of all blood cells throughout life. A major challenge in the field is the inability to culture HSCs without compromising self-renewal. My goal was to reconstruct an optimal hematopoietic niche from mesodermal differentiation of human pluripotent stem cells (hPSC) to facilitate the maintenance of functional HSCs. Initial characterization of the human fetal bone marrow and adult adipose tissues revealed that a subpopulation of CD146+ perivascular cells was capable of supporting the self-renewal of transplantable human cord blood HSCs ex vivo. Vector integration site-based lineage tracing technology was utilized to gain insights into the stages through which hPSC differentiate into mesodermal derivatives of the HSC niche. High throughput sequencing revealed the presence of mesodermal progenitors with trilineage (hematopoietic, endothelial and mesenchymal) potential during hPSC differentiation and uncovered the lineage bifurcation of hematopoietic and mesenchyme early on in separated bipotent populations. The hPSC-derived mesenchymal populations were further studied in relation to their ability to promote or inhibit HSC maintenance, leading to the discovery of a population that was phenotypically, functionally and molecularly similar to primary human perivascular cells of the HSC niche. These findings elucidated lineage commitment events during early human embryogenesis and informed strategies to optimize the therapeutic development of cell lineages from hPSC.