The Human Blood Hierarchy Is Shaped By Distinct Progenitor Lineages Across Development
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».