Traditionally, hematopoietic stem cell transplant (HSCT) has been thought of as a “hard reboot” of the hematopoietic system, effectively removing the offending cells to start over. HSCT is commonly performed for a variety of malignant, genetic, and autoimmune conditions.1,2 In HSCT, bone marrow or peripheral blood stem cells from a human donor are introduced after chemoablation of the recipient. For approximately one week afterward, the bone marrow remains acellular, and blood cell counts are low; however, in the ensuing weeks and months, the donor stem cells engraft in the recipient’s marrow space and regenerate normal marrow elements, resulting in eventual recovery of peripheral blood counts by cells derived entirely from the donor’s hematopoietic cells.3
At baseline, a human is estimated to have approximately 10,000 hematopoietic stem cells (HSCs), with 10% contributing to hematopoiesis at any given time.4,5 Stem cells divide slowly (approximately once every 40 days) when compared with other hematopoietic precursors and are thus more likely to be quiescent.4 Although a large quantity of HSCs are transferred during HSCT, the number is considerably lower than the normal number in the recipient. Therefore, reconstitution of the marrow space is believed to occur through gradual expansion of the HSC population and more rapid division of the differentiating elements.6 Peripheral blood cell lineages recover eight to 40 days after HSCT, with the absolute neutrophil count reaching a normal level at approximately two to four weeks.7,8 In contrast, a fully functional adaptive immune system (B and T lymphocytes) is often not observed until months or years following transplantation.8 In past studies, researchers have postulated that reconstitution of the bone marrow occurs in stages,6 whereby an initial “first responder” population of committed immature cells generates early neutrophil recovery. As HSC progeny had not been previously identified in the blood in the early post-HSCT phase, the authors speculated that the donor HSCs only contributed to hematopoiesis in later stages (i.e., ≥7 weeks after HSCT). However, these prior studies were limited to animal models and small-scale human clinical trials and lacked the sensitivity to detect small HSC-derived cell populations.9-11
Stefan Radtke, PhD, and colleagues challenged this paradigm using a system that tracks retroviral integration sites (“bar-coding”) for HSCs in a non-human primate model of HSCT. By tracking hematopoietic reconstitution over time, they were able to track the contributions of individual HSC clones, observing that HSCs contributed to reconstitution earlier than previously hypothesized. They were additionally able to observe the gradual transition of the transplanted HSC population from a diverse population to more clonally restricted HSC pools, suggesting that stem cells undergo symmetric expansion to generate two daughter stem cells. They mathematically modeled a system in which, by random chance, each stem cell would undergo either (1) symmetric cell differentiation into two progenitor (early-differentiating) cells, (2) symmetric cell expansion into two HSCs, or (3) asymmetric cell division into one HSC and one progenitor cell. This model suggests that some HSCs contribute to early engraftment by quickly generating differentiating progenitor cells, while other HSCs undergo expansion that eventually maintains hematopoiesis at later time points (Figure). The HSCs that symmetrically expand to create many stem cells lead to a predominance of more restricted HSC clones in the long-lived bone marrow. Conversely, the HSCs that symmetrically differentiate into non-HSC progenitor cells support immediate peripheral blood reconstitution but will ultimately be lost from the long-lived HSC population.
By longitudinally sampling the engrafting hematopoietic cells in a non-human primate model of HSCT, Dr. Radtke and colleagues demonstrated that transplanted HSCs can simultaneously expand and differentiate (Figure), challenging the prior paradigm of limited stem cell division. This new insight raises the possibility of a more “nimble” HSC population that responds to hematopoietic needs. For example, HSCs dividing in a replete marrow space may be less likely to undergo symmetric division into two daughter HSCs, limiting hematopoietic expansion. This exciting possibility may one day allow the positive or negative selection of specific HSC populations, such as gene-therapy-altered HSCs or HSCs bearing pre-neoplastic CHIP mutations, respectively. However, the mechanisms that guide symmetric versus asymmetric HSC division and how this apparently stochastic process may be altered remain unclear. Nevertheless, this new model underscores the dynamic proliferative capability of HSCs, allowing us to better understand their behavior in the setting of HSCT. In the future, we may eventually be able to manipulate HSC engraftment in the recipient to tailor for individual HSCT applications.
Dr. Hasserjian reports receiving consulting income from Bluebird Bio. Dr. Wilton indicated no relevant conflicts of interest.