The Human Blood Hierarchy Is Shaped By Distinct Progenitor Lineages Across Development
Bibliographic record
Abstract
Abstract Background: The hematopoietic roadmap is a compilation of the various lineage differentiation routes that a stem cell takes to make blood. On several occasions over the last six decades, the murine roadmap has been reconceived due to new information overturning old dogmas. The human roadmap, which describes the extraordinary throughput of more than three hundred billion cells daily has changed little, with the classical model of hematopoiesis still prevailing. In this model, blood differentiation initiated at the level of stem cells must pass through a series of increasingly lineage-restricted oligopotent and then unipotent progenitor intermediates. As cellular differentiation flows from stem cells to unipotent cells, the oligopotent progenitors are the quintessential step where lineage choices are consolidated. One such critical oligopotent intermediate is the common myeloid progenitor (CMP), believed to be the origin of all myeloid (My), erythroid (Er) and megakaryocyte (Mk) cells. While murine studies are beginning to challenge the existence of oligopotent progenitors, a comprehensive analysis of human myelo-erythroid differentiation is lacking. Moreover, whether the pool of oligopotent intermediates is fixed across human development is unknown. The classical roadmap is the only guide that describes human hematopoiesis and consequently our view of blood homeostasis and disease is intimately tied to this conception. Rationale: The differentiation roadmap 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 timepoints in human blood development: fetal liver (FL), neonatal cord blood (CB) and adult bone marrow (BM). Using a new cell-sorting scheme based on markers linked to Er and Mk lineage specification (CD71 and BAH1), we found that previously described populations of multipotent progenitors (MPPs), CMPs, and megakaryocyte-erythroid progenitors (MEPs) were considerably heterogeneous and could be further purified beyond current definitions. 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 of adult BM leading to the conclusion that multipotent cells differentiate into unipotent cells directly. Mk-Er activity predominately arose in the stem cell compartment at all developmental timepoints. 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, a striking 80% of single-cell clones with Mk activity were derived from a novel progenitor in the stem cell compartment, although less potent Mk progenitors were also present in the progenitor compartment. Interestingly, 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 roadmaps 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. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".