Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals

Abstract

Summary Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in the adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses.

Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly

“…[1][2][3][4] Skewing can be seen in all hematopoietic lineages, consistent with an origin in HSCs, but is most easily seen in nucleated cells of the myeloid lineage because they are short lived and require continuous replenishment from HSCs. 5,6 Age-related CH does not arise from a simple depletion of HSCs, as the abundance of HSCs in human bone marrow actually increases in older people. 7 Skewed X-inactivation also occurs in myeloid neoplasias, including acute myelogenous leukemia (AML), myelodysplastic syndromes, and myeloproliferative disorders.…”

Tracing human stem cell lineage during development using DNA methylation

“…Direct tracking of stem cell lineage and diversity has been achieved in experimental animal models by enumerating chromosomal translocations, retroviral insertions and molecular barcodes in repopulating cells during hematopoietic reconstitution (Eaves 2015). Most recently, lineage tracing studies using genetically labeled HSCs, which permits stem cell tracking without engraftment, have produced contrasting data on the relative contributions of HSCs and progenitors in steady state hematopoiesis (Sun et al 2014b;Busch et al 2015;Sawai et al 2016;Säwén et al 2016;McKenna et al 2016). At the same time, because genetic lineage tracing is not feasible in humans, effective strategies for identifying and defining markers capable of capturing both progenitor and stem cell lineages in human populations remain to be developed.…”

Sca-1 expression level identifies quiescent hematopoietic stem and progenitor cells

“…The latter was surprising, as steady-state type I IFN partially accounted for SCA-1 expression ( Figure S2G) and ''tonic'' (basal or constitutive) type I IFN signaling has been implied in HSC maintenance (Gough et al, 2012 Hematopoietic contribution, differentiation pattern, and the relationship between the HSPC subpopulations and diverse SCA-1 expression have not been addressed in situ so far. We speculate that discrepancies between recent studies reporting high (Sawai et al, 2016) or low (Busch et al, 2015;Schoedel et al, 2016;Sun et al, 2014) contribution of HSCs to steady-state hematopoiesis might reflect lineage tracing of exclusive HSC subpopulations that differ by SCA-1 expression and cell-cycle activity.…”