Stochastic fate decisions of HSCs after transplantation: early contribution, symmetric expansion, and pool formation

• Published in: Blood Vol. 142; no. 1; pp. 33 - 43
• Main Authors: Radtke, Stefan, Enstrom, Mark, Pande, Dnyanada, Duke, Elizabeth R., Cardozo-Ojeda, E. Fabian, Madhu, Ravishankar, Owen, Staci, Kanestrom, Greta, Cui, Margaret, Perez, Anai M., Schiffer, Joshua T., Kiem, Hans-Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.07.2023; The American Society of Hematology
• Subjects: Animals; Clone Cells; Hematopoiesis; Hematopoiesis and Stem Cells; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2022018564

•HSCs contribute to neutrophil recovery.•HSCs symmetrically divide, forming clonal pools. [Display omitted] Hematopoietic stem cells (HSCs) are assumed to be rare, infrequently dividing, long-lived cells not involved in immediate recovery after transplantation. Here, we performed unprecedented high-density clonal tracking in nonhuman primates and found long-term persisting HSC clones to actively contribute during early neutrophil recovery, and to be the main source of blood production as early as 50 days after transplantation. Most surprisingly, we observed a rapid decline in the number of unique HSC clones, while persisting HSCs expanded, undergoing symmetric divisions to create identical siblings and formed clonal pools ex vivo as well as in vivo. In contrast to the currently assumed model of hematopoietic reconstitution, we provide evidence for contribution of HSCs in short-term recovery as well as symmetric expansion of individual clones into pools. These findings provide novel insights into HSC biology, informing the design of HSC transplantation and gene therapy studies. Radtke and colleagues challenge the dogma that hematopoietic stem cells (HSC) are rare, infrequently dividing, and do not contribute to early mature cell production following hematopoietic cell transplantation. The authors demonstrate using high-density clonal tracking that HSC clones appear early after transplant and are the main source of early blood cell production. Furthermore, the number of individual HSC clones rapidly declines with time, with long-term reconstitution resulting from a smaller number of expanding HSC clones.