Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium

Abstract

Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta–gonad–mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.

Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells

“…How do different anterior-posterior identities in ECs exert far-reaching effects on their ability to subsequently produce HSCs or hematopoietic progenitors? Our work supports a model that individual ECs are diverse, and only some are competent to generate HSCs, 47 , 183 , 184 which we hypothesize may reflect the diverse primitive streak origins of these different ECs.…”

Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life

“…During development, a nascent population of HSCs must grow large enough to entirely support hematopoiesis by birth. We model a population of N clone cells that grows to a size of N cell cells, by either uniform or frequency-dependent growth 15,34 (Fig 1A). The variation observed between pairs of twins/unrelated individuals at birth (Fig.…”

“…Weak selection and slow expansion suggest that HSC subclones can arise early in life, potentially even before birth, with explained initial growth spurts 1,10,[13][14][15] . Such early acquisition of a selective advantage eventually leading to CH would explain two open questions about CH without the need for identifiable driver mutations.…”

MiR-128-3p – a gray eminence of the human central nervous system

“…Conversely, miR-128-3p targets numerous factors that maintain the "stemness" of cancer cells, including epigenetic regulators and master kinases that can act genome-wide and transcriptome-wide, thus curbing their tumorigenicity. 144 Thus, the therapeutic usage of miR-128-3p is not without controversy, as it exhibits divergent effects depending on specific contexts and target co-expression genes and thus can be regarded as a "double-edged sword" in CNS disease therapy.…”