To maintain the enormous daily hematopoietic cell output (approximately 1 x 1012 cells/day), terminally differentiated blood cells are continually produced from highly proliferative but short-lived progenitors, which in turn arise from a rare population of quiescent hematopoietic stem cells (HSCs). Understanding how individual HSCs contribute to blood cell formation throughout a lifetime has remained a subject of debate. In this paper, McKenzie and colleagues studied individual human HSCs and found substantial variation in proliferation kinetics and self-renewal capacity implying that HSC fate is unpredictable before they enter the more rigid downstream developmental programs.
In Brief
Hematopoietic cell repopulation following sublethal irradiation of the nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse has emerged as the “gold standard” surrogate assay for studying human HSCs. The human cells that repopulate these mice are functionally defined as “SCID mouse-repopulating cells” (SRCs). SRCs express CD34 and are lineage-negative (Lin-), and distinct SRC activities can be found in the CD38- and CD38lo subfractions. McKenzie and colleagues generated more than 600 individual human SRCs from placental and umbilical tissues that were transduced with a lentivirus to track the clonal ancestry of the human cells after injection and evaluated their repopulating activity and self-renewal over a seven-month period of analysis in serially transplanted NOD-SCID mice. Primary transplant recipients showed that only a subset of clones in the injection site (right femur) were also present in other bones, indicating that only some SRCs divided and migrated to other hematopoietic tissues. Individual SRCs collected from primary recipients were heterogeneous in terms of self-renewal, with some clones making substantial yet fluctuating contributions over time to all hematopoietic territories and cells of secondary mice, and others not engrafting after serial transplantation. Evidence that clonally related daughter cell pairs have distinct and unpredictable repopulation kinetics provides the strongest support favoring this stochastic model for hematopoiesis.
The paper by McKenzie and colleagues successfully brings together a wide range of experimental methodologies to now address the key issue of how human HSCs act in vivo. The considerable heterogeneity among stem cell fate and self-renewal implies that this unpredictability likely arises through HSC interactions with as-of-yet undefined extrinsic properties (i.e., HSC niche occupancy and cytokine exposure) or intrinsic properties (i.e., asymmetric distribution of intracellular proteins and alterations of signal transduction pathways). If HSC self-renewal and proliferation kinetics are governed by probabilistic elements, then the current strategies to identify a molecular stem cell signature by profiling global gene expression of pooled yet static HSC populations may prove unreliable. Also, as the resemblance between normal and malignant stem cells deepens, the understanding of how stem cell behavior can be modulated by extrinsic and intrinsic factors will identify novel targets for cancer therapeutics.
Competing Interests
Dr. Lowsky indicated no relevant conflicts of interest.
