Our research interests
Decoding mechanisms driving blood stem cell heterogeneity from the embryonic endothelium.
Stem cell populations across tissues, long thought to be homogeneous, have in fact been identified as heterogeneous. Heterogeneity is defined by diverse phenotypic and functional cell characteristics. Stem cell heterogeneity must be properly regulated, or it can lead to lineage-biased progeny and a decreased capacity to repopulate tissues during regeneration. Thus, this presents a significant impediment in biomedical research.
Hematopoietic stem cells are heterogenous. Single-cell sequencing analyses show that adult hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous mixture of multipotent stem and progenitor cells that differ in cell cycle status, transcriptional lineage priming, and blood lineage outputs. Reprogramming of somatic cells to HSPCs has been the holy-grail for autologous transplantation, a lifesaving therapy against a variety of blood cancers
These cells show variation in self-renewal kinetics and lineage priming biases that can compromise the balanced reconstitution of blood and immune cells after transplantation. Diverse HSPC phenotypes are observed during development in the aorta gonad mesonephros (AGM) of the embryo, where HSPCs are first made. These data suggest that HSPCs are “born heterogeneous”. However, the basis of this intrinsic heterogeneity of HSPCs remains unknown. Uncovering this mechanism will help inform new strategies to regulate HSPC phenotypes ex-vivo and in-vivo.
Foundational findings
We discovered that signaling in endothelial cells, before the endothelial to hematopoietic transition, regulates HSPC heterogeneity in the embryo and adult zebrafish (Nat Cell Bio, 2023). We found that loss of the microRNA in endothelial cells, miR-128, alters the composition of these HSPC states. miR-128 directly inhibits the activity of Wnt- and Notch-signaling in endothelial cells. Mechanistically, single cell RNA-sequencing revealed that Wnt regulation, instructs the transdifferentiation of replicative and erythroid biased HSPCs. In contrast, Notch regulation programs lymphoid biased HSPCs. These results showed that co-ordinate regulation of multiple signaling pathways in endothelial cells, ultimately controls HSPC heterogeneity.
In the Ghersi lab, we will explore how post-transcriptional and transcriptional mechanisms regulate HSPC heterogeneity at birth. We plan to achieve this goal by uncovering the intrinsic and extrinsic complex regulation in endothelial cells that regulates HSPC heterogeneity.
Deciphering extrinsic regulation in the embryonic endothelium controlling HSPC heterogeneity.
We found that Wnt- and Notch-signaling regulate HSPC heterogeneity but how these pathways interact with each other and how they drives HSPC heterogeneity is still not well understood. This presents difficulties in producing ex vivo HSPCs. We believe that the regulation of Wnt and Notch is more complex than what is known. Moreover, we identified other signaling pathways that are also de-regulated by miR-128. We hypothesize that signaling pathway interactions, such as Wnt, Notch and others dictate HSPC heterogeneity formation in endothelial cells.
This discovery will inform the signaling strategy to engineered blood stem cells production ex vivo as well as learn more on normal hematopoiesis in vivo.
Uncovering intrinsic regulation of HSPC heterogeneity in endothelial cells.
Formation of heterogenous HSPCs via the endothelial to hematopoietic transition (EHT) through endothelial-signaling suggests the existence of un-appreciated EHT paths. Endothelial cells are very diverse in development, via their cellular identity and their spatio-temporal existence. We hypothesize that endothelial cells that transition into HSPCs are not a homogenous population but rather heterogeneous.
Altogether this work will establish new paradigms underlying the inheritance of HSPC heterogeneity.