Ontogenic shifts in cellular fate are linked to proteotype changes in lineage-biased hematopoietic progenitor cells

Abstract

Highlights d >4,000 proteins quantified in fetal and adult hematopoietic progenitor cells (HPCs) d Protein expression in HPCs separates cells based on ontogenic stage and lineage potential d Generic fetal features are suppressed in myeloid-restricted progenitors d Low Irf8 expression partially drives an impairment in monopoiesis in fetal HPCs

Transcriptional reprogramming in neonatal hematopoietic stem and progenitor cells

“…Some innate immune cells (e.g., peritoneal B1 B cells and gd T cells) arise almost exclusively from fetal HSCs [16−19]. Phenotypic MPP and HPC subpopulations also have distinct lineage outputs during fetal and adult stages [20,21]. These observations suggest that hematopoietic progenitors must undergo considerable transcriptional and epigenetic reprogramming between birth and adulthood.…”

The Opportunity of Proteomics to Advance the Understanding of Intra- and Extracellular Regulation of Malignant Hematopoiesis

“…Irf8 is a highly important regulator of lineage choices between neutrophils, monocytes and dendritic cells (DCs), and represents an example of a TF driving lineage commitment in a dose-dependent manner; lack of this TF promotes neutrophil generation whereas low and high levels drive differentiation towards inflammatory Ly6C + monocytes and DCs, respectively ( Murakami et al, 2021 ). In line with this, fetal granulocyte-monocyte progenitors (GMPs), which express low levels of Irf8 protein ( Jassinskaja et al, 2021 ), have limited potential to produce fully mature inflammatory monocytes compared to adult GMPs. Intriguingly, a recent study comparing human FL and fetal bone marrow hematopoiesis revealed that myeloid potential is remarkably low in the former relative to the latter ( Popescu et al, 2019 ; Jardine et al, 2021 ), further highlighting the differential lineage bias of HSPCs derived from different stages of ontogeny.…”

“…While myeloid potential is nearly completely lost at the CLP stage of lymphopoiesis in vivo , myeloid programs have been shown to be partially reactivated during ex vivo culture of adult CLPs under lymphomyeloid differentiation conditions ( Richie Ehrlich et al, 2011 ). We have recently shown that this is not the case for fetal CLPs, which retain lymphoid restriction in the presence of myelopoiesis-promoting cytokines in culture, and, accordingly, express lower levels of proteins associated with myelopoiesis than their adult counterparts ( Jassinskaja et al, 2021 ).…”

“…Several bodies of recent work, including studies performed in our lab, have shown that cellular processes such as metabolism, response to inflammation and even malignant transformation are regulated post-transcriptionally in HSPCs ( Cabezas-Wallscheid et al, 2014 ; Haas et al, 2015 ; Jassinskaja et al, 2017 , 2021 ; Raffel et al, 2020 ). Furthermore, adult HSCs, which are hallmarked by a low protein synthesis rate ( Signer et al, 2014 ), have recently been shown to have a significantly higher rate of transcription compared to more downstream hematopoietic progenitor cells (HPCs) ( Mansell et al, 2021 ).…”

Hematopoiesis during Ontogenesis, Adult Life, and Aging

“…It should finally be noted that fetal and adult HSPCs demonstrate significant differences in several key functional aspects such as cell cycle kinetics [29][30][31], response to inflammatory stress, and the production of various subpopulations of blood and immune cells [32].…”