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Functional and molecular profiling of hematopoietic stem cells during regeneration

ABSTRACT: Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. While mouse HSCs have been well studied during homeostatic conditions, the mechanisms regulating HSC activation during stress remain unclear. Here, we analyzed the different phases of regeneration following transplantation. We isolated bone marrow from mice at eight time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs and the progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE241088 | GEO | 2023/10/31

REPOSITORIES: GEO

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Project description:In this study we investigated the effect of Slfn2 loss of function in the murine hematopoietic system. We chose to evaluate gene expression differences in multipotent progenitors, as this population was found to be diminshed in elektra homozygous mice, additionally the MPP population also displayed increased cell cycling compared to wildtype and increased apoptosis. Abstract from associated publication copied in below, from Warsi et al. 2022 Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells, published in Haematologica. DOI 10.3324/haematol.2021.279799 Even though hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. To investigate the role of Slfn2 in the regulation of HSCs we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSCs resulted in a significantly reduced regenerative capacity of HSCs in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSCs (as compared to WT HSCs) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of a dult HSCs and HSC quiescence.

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Functional and molecular profiling of hematopoietic stem cells during regeneration

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