DISTINCT ROUTES OF LINEAGE DEVELOPMENT RESHAPE THE HUMAN BLOOD HIERARCHY ACROSS ONTOGENY

By F. Notta, Sasan Zandi, N. Takayama, Stephanie M. Dobson, O. Gan, Gavin W. Wilson, K. Kaufmann, Jessica McLeod, E. Laurenti, Cyrille F. Dunant and 4 more. Science, 2015

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Adjusting hematopoietic hierarchy In adults, more than 300 billion blood cells are replenished daily. This output arises from a cellular hierarchy where stem cells differentiate into a series of multilineage progenitors, culminating in unilineage progenitors that generate over 10 different mature blood cell types. Notta et al. mapped the lineage potential of nearly 3000 single cells from 33 different cell populations of stem and progenitor cells from fetal liver, cord blood, and adult bone marrow (see the Perspective by Cabezas-Wallscheid and Trumpp). Prenatally, stem cell and progenitor populations were multilineage with few unilineage progenitors. In adults, multilineage cell potential was only seen in stem cell populations. Science, this issue p. 10.1126/science.aab2116; see also p. 126 As humans age, progenitor cells take over from stem cells the task of producing a steady supply of blood cells. [Also see Perspective by Cabezas-Wallscheid and Trumpp] INTRODUCTION The hematopoietic road map is a compilation of the various lineage differentiation routes that a stem cell takes to make blood. This program produces greater than 10 blood cell fates and is responsible for generating more than 300 billion cells daily. On several occasions over the past six decades, the murine road map has been reconceived due to new information overturning dogma. However, the human road map has changed little. In the human model, blood differentiation initiates at the level of multipotent stem cells and passes through a series of increasingly lineage-restricted oligopotent and, finally, unipotent progenitor intermediates. One critical oligopotent intermediate is the common myeloid progenitor (CMP), believed to be the origin of all myeloid (My), erythroid (Er), and megakaryocyte (Mk) cells. Although murine studies challenge the existence of oligopotent progenitors, a comprehensive analysis of human My-Er-Mk differentiation is lacking. Moreover, whether the pool of oligopotent intermediates is fixed across human development (fetal to adult) is unknown. RATIONALE The differentiation road map taken by human hematopoietic stem cells (HSCs) is fundamental to our understanding of blood homeostasis, hematopoietic malignancies, and regenerative medicine. RESULTS We mapped the cellular origins of My, Er, and Mk lineages across three time points in human blood development: fetal liver (FL), neonatal cord blood (CB), and adult bone marrow (BM). Using a cell-sorting scheme based on markers linked to Er and Mk lineage specification (CD71 and CD110), we found that previously described populations of multipotent progenitors (MPPs), CMPs, and megakaryocyte-erythroid progenitors (MEPs) were heterogeneous and could be further purified. Nearly 3000 single cells from 11 cellular subsets from the CD34+ compartment of FL, CB, and BM (33 subsets in total) were evaluated for their My, Er, and Mk lineage potential using an optimized single-cell assay. In FL, the ratio of cells with multilineage versus unilineage potential remained constant in both the stem cell (CD34+CD38–) and progenitor cell (CD34+CD38+) enriched compartments. By contrast, in BM, nearly all multipotent cells were restricted to the stem cell compartment, whereas unilineage progenitors dominated the progenitor cell compartment. Oligopotent progenitors were only a negligible component of the human blood hierarchy in BM, leading to the inference that multipotent cells differentiate into unipotent cells directly by adulthood. Mk/Er activity predominantly originated from the stem cell compartment at all developmental time points. In CB and BM, most Mks emerged as part of mixed clones from HSCs/MPPs, indicating that Mks directly branch from a multipotent cell and not from oligopotent progenitors like CMP. In FL, an almost pure Mk/Er progenitor was identified in the stem cell compartment, although less potent Mk/Er progenitors were also present in the progenitor compartment. In a hematological condition of HSC loss (aplastic anemia), Mk/Er but not My progenitors were more severely depleted, pinpointing a close physiological connection between HSC and the Mk/Er lineage. CONCLUSION Our data indicate that there are distinct road maps of blood differentiation across human development. Prenatally, Mk/Er lineage branching occurs throughout the cellular hierarchy. By adulthood, both Mk/Er activity and multipotency are restricted to the stem cell compartment, whereas the progenitor compartment is composed of unilineage progenitors forming a “two-tier” system, with few intervening oligopotent intermediates. Roadmaps of human blood stem cell differentiation. The classical model envisions that oligopotent progenitors such as CMP are an essential intermediate stage from which My/Er/Mk differentiation originates. The redefined model proposes a developmental shift in the progenitor cell architecture from the fetus, where many stem and progenitor cell types are multipotent, to the adult, where the stem cell compartment is multipotent but the progenitors are unipotent. The grayed planes represent theoretical tiers of differentiation. In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult “two-tier” hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.

Subfields: Hematology, Physiology

View Paper: https://www.semanticscholar.org/paper/a629b42e6a0d426bc29d23fe231d246ae74d7762

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Citations in the corpus

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes and progenitors (2017, result): “Although CD100CD34 cells were CD117/KITCD45RA andCSF1R/CD115, CD1C,CD141, CD123—aprofile similar to that of a previously reported circulating humanDCprogenitor (24, 27, 28)—they differ from the published progenitor in having amore primitivemorphology and lacking CSF2R/CD116 and FLT3/CD135 expression”
Allelic Landscape of Human Blood Cell Trait Variation and Links (2016, background): “Themolecular programs that control hematopoietic stem cell differentiation and proliferation are incompletely understood (Notta et al., 2016; Paul et al., 2015).”
Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation (2018, background): “Furthermore, recent work measuring single-cell transcriptomes has revealed significant transcriptional heterogeneity in isolated progenitors (Notta et al., 2016) and across differentiation (Laurenti and Göttgens, 2018; Velten et al., 2017).”
A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation. (2016, result): “Although this observation is at odds with the more traditional view of the hematopoietic lineage tree,(54) it is consistent with recent analysis of both mouse and human cell fate diversification.(41,53,55) Importantly, we now provide for the first time a reconstructionof the likely dynamicsof expres”
Lineage tracing on transcriptional landscapes links state to fate during differentiation (2018, background): “However, recent state maps from scSeq (9), as well as clonal studies using barcodes (10) and single-cell culture (11), suggest that the traditional intermediate cell types are internally heterogeneous in state and fate potential, with HSPCs lying along a continuum of states rather than a stepwise hi”
Fundamental limits on dynamic inference from single-cell snapshots (2017, background): “However, the precise tree remains controversial (27, 28), since existing measurements of fate potential reflect a patchwork of defined HPC subsets that may have internal heterogeneity (29) and provide only incomplete coverage of the full HPC pool.”