Tissue-specific and stress-related heterogeneity in the adult human haematopoietic stem cell pool
Hematology, Oncology
Final Report Abstract
Hematopoietic stem and progenitor cells (HSPCs) are crucial for life-long blood production. Imbalances in HSPCs composition and function can lead to the altered hematopoietic phenotypes associated with stress, age and disease. Especially in adult humans, HSPCs composition and molecular regulation is poorly understood. This project aimed at comprehensively characterizing the cellular, functional and molecular HSPC heterogeneity within different adult human hematopoietic tissues at single-cell resolution, both at steady state and under stress conditions. I found that HSPCs of extramedullary sites (peripheral blood (PB) and spleen) significantly differ from bone marrow (BM) HSPC pools. First, in contrast to actively dividing BM HSPCs, extramedullary tissues are enriched for low-tonon proliferating early progenitors, suggesting no considerable ongoing hematopoiesis at these sites at steady state. Second, the vast majority of hematopoietic stem cells/multipotent progenitors (HSCs/MPPs) from spleen, PB, and mobilized PB share a common transcriptional signature and increased abundance of lineage-primed subsets compared with BM. Third, I uncovered that steady-state PB is uniquely biased toward erythroid-megakaryocytic differentiation. This is imparted by phenotypic CD71+ HSCs/MPPs, which are enriched in PB but rare in other adult tissues and are functionally skewed to exclusively produce erythrocytes and megakaryocytes. Importantly, however, this study also shows that extramedullary HSPCs function and composition can change with stress and disease. I provide proof-of-principle evidence that splenic HSPCs can participate in red blood cell production in humans, albeit likely limited, in a clinical condition of high erythroid demand (hereditary spherocytosis). More interestingly, I also show that the unique erythroid/megakaryocyte bias of PB HSPCs becomes imbalanced with age, chronic anemia (b-thalassemia) and myeloproliferative neoplasm (essential thrombocythemia). This suggests that HSPCs from PB, although being strikingly different to those in BM, faithfully report impairments of hematopoiesis making them potential clinical indicators of BM dysfunction. Both Aims of the original research proposal were met with the presented results. However, preliminary finding in Aim 2 made me change the line of research slightly. Instead of studying the human HSPC response to frequent platelet donation, I explored their response to hematopoietic stress caused by physiological ageing and multiple blood disorders. Overall, the results of this project provide a comprehensive resource of HSPC landscapes across the main hematopoietic sites in adult humans. All data is published and can be browsed on two interactive web portals. In particular, this research highlights the relevance of extramedullary HSPCs in adult humans and provides a healthy baseline of steady-state PB HSPC composition. It also emphasizes that examination of PB HSPC composition and function can be a valuable clinical indicator for screening and monitoring of disease.
Publications
- (2021). Blood and immune development in human fetal bone marrow and Down syndrome. Nature 598, 327–331
Jardine, L., Webb, S., Goh, I., Quiroga Londoño, M., Reynolds, G., Mather, M., Olabi, B., Stephenson, E., Botting, R.A., Horsfall, D., et al.
(See online at https://doi.org/10.1038/s41586-021-03929-x) - (2021). Hematopoietic stem and progenitor cells outside the bone marrow: where, when, and why. Experimental Hematology
Mende, N., and Laurenti, E.
(See online at https://doi.org/10.1016/j.exphem.2021.10.002) - (2021). Single-cell multi-omics analysis of the immune response in COVID-19. Nat Med 27, 904–916
Stephenson, E., Reynolds, G., Botting, R.A., Calero-Nieto, F.J., Morgan, M.D., Tuong, Z.K., Bach, K., Sungnak, W., Worlock, K.B., Yoshida, M., et al.
(See online at https://doi.org/10.1038/s41591-021-01329-2) - (2022). Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans. Blood
Mende, N., Bastos, H.P., et al.
(See online at https://doi.org/10.1182/blood.2021013450)
