Definitive hematopoietic stem cells minimally contribute to embryonic hematopoiesis

Abstract

Hematopoietic stem cells (HSCs) are rare cells that arise in the embryo and sustain adult hematopoiesis. Although the functional potential of nascent HSCs is detectable by transplantation, their native contribution during development is unknown, in part due to the overlapping genesis and marker gene expression with other embryonic blood progenitors. Using single-cell transcriptomics, we define gene signatures that distinguish nascent HSCs from embryonic blood progenitors. Applying a lineage-tracing approach to selectively track HSC output in situ, we find significantly delayed lymphomyeloid contribution. An inducible HSC injury model demonstrates a negligible impact on larval lymphomyelopoiesis following HSC depletion. HSCs are not merely dormant at this developmental stage, as they showed robust regeneration after injury. Combined, our findings illuminate that nascent HSCs self-renew but display differentiation latency, while HSC-independent embryonic progenitors sustain developmental hematopoiesis. Understanding these differences could improve de novo generation and expansion of functional HSCs.

Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration

“…Mac 8 population was enriched in myh7l and tnnt2a, which are typical CM markers, and this result was in line with a previous study in mouse showing that cardiomyocyte signature is specifically expressed in murine cardiac CX3CR1 + resident macrophages (81). Mac 9 expressed kita, tcf12, and csf1ra, resembling the myeloid progenitors identified in mouse and zebrafish embryonic stage (82)(83)(84). Unlike heterogeneous macrophages, neutrophils were classified into just two populations Neu 1 and Neu 2, which commonly express mmp9, mmp13a.1, npsn, scpp8, lect2l, tcnbb and il1b genes (Figure 2C).…”

Making Blood from the Vessel: Extrinsic and Environmental Cues Guiding the Endothelial-to-Hematopoietic Transition

“…The capacity of cells formed via EHT to renew themselves or generate cells of the erythroid, myeloid and lymphoid lineages throughout the lifetime of the animal distinguishes select progenitors as HSCs. It is important to note that more lineage-restricted definitive progenitors have been documented to arise via EHT events both before and concurrent with HSC emergence, and new transcriptomic and lineage-tracing data from zebrafish suggests that embryonic blood production primarily occurs from these cell types (with the HSC pool being drawn on later in adult life) [8]. These include lymphoid progenitors from the caudal DA in zebrafish [9,10], murine lympho-myeloid progenitors [11,12] and erythro-myeloid restricted progenitors (EMPs) in the zebrafish trunk [13] and from yolk sac arteries in mice [14].…”

“…Excitingly, empirical data from live imaging in zebrafish are being combined with mathematical modeling to predict tissue mechanics in the DA during HSPC formation which may instruct where these events occur [108,109]. Additionally, cell tracing studies, such as those recently described by Ulloa et al [8], can help distinguish whether the different types of stem and progenitor populations that are produced by EHT may be differentially impacted by blood flow and/or intra-and extracellular structural dynamics. Future work may also clarify exactly when the flow-dependence of the EHT process is relieved, and precisely when the contractile machinery is used for morphogenetic movements vs. fate acquisition.…”

In the spotlight: the role of TGFβ signalling in haematopoietic stem and progenitor cell emergence

“…Linking data from the growing number of single cell transcriptional profiling studies in HE/HSPCs (e.g. [73][74][75][76][77]) with further studies on the exact composition of SMAD complexes will help address these questions. Chromatin binding data for the individual Smad proteins in HE or HSPC/HSCs would be desirable, but will remain a challenge to perform in low cell number samples until good antibodies and new alternatives to conventional ChIP such as Cut&Tag [78] are standardised.…”