Blood Stem Cell Hierarchy

Blood stem cells seem to have preferences to what they will differentiate into, including the “multipotent” stem cells that typically have the potential to become many cell types.  There seems to be a “hierarchy” of such stem cells, which may have implications for stem cell therapies.  Abstract:

Rare multipotent hematopoietic stem cells (HSCs) in adult bone marrow (BM) with extensive self-renewal potential possess the ability to efficiently replenish all myeloid and lymphoid blood cells, securing long-term multilineage reconstitution following physiological and clinical challenges, including chemotherapy and hematopoietic transplantations. HSC transplantation remains the only curative treatment for many hematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality. Single cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs, supported by findings in unperturbed hematopoiesis and suggested to reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid- and platelet-biased HSCs. Other studies suggested that such lineage bias might reflect generation within the phenotypic HSC compartment of unipotent or oligopotent self-renewing progenitors, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency. Here, highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid, B and T cell lineages produced from singly transplanted HSCs revealed a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not other blood cell lineages, despite sustained multipotency, whereas no HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage tracing supports an important role of platelet-biased HSCs also in unperturbed adult hematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, prior to loss of self-renewal and multipotency.