Biology subjects

Somuncular, E.

Publications and source records attributed to Somuncular, E..

3 recordsLinked to original sources

bioRxiv2023

Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets

Age is a risk factor for hematologic malignancies. Attributes of the aging hematopoietic system include increased myelopoiesis, impaired adaptive immunity, and a functional decline of the hematopoietic stem cells (HSCs) that maintain hematopoiesis. Changes in the composition of diverse HSC subsets have been suggested to be responsible for age-related alterations, however, the underlying regulatory mechanisms are incompletely understood in the context of HSC heterogeneity. In this study, we investigated how distinct HSC subsets, separated by CD49b, functionally and molecularly change their behavior with age. We demonstrate that blood lineage differentiation progressively shifts to a higher myeloid cellular output in both lymphoid-biased and myeloid-biased HSC subsets during aging. In parallel, we show that HSCs selectively undergo age-dependent gene expression and gene regulatory molecular changes in a progressive manner, which is initiated already in the pre-adult stage. Overall, our studies suggest that aging intrinsically alters both cellular and molecular properties of HSCs. HighlightsO_LIWith age a gradual shift towards myeloid differentiation occurs in both myeloid-biased and lymphoid-biased enriched HSC subsets. C_LIO_LIAge-related molecular changes preferentially occur in HSCs. C_LIO_LIFunctionally distinct HSC subsets with high transcriptional similarity can be distinguished on the epigenetic level. C_LIO_LIHSC aging is associated with a progressive increase in chromatin accessibility. C_LI

cell biology↗

bioRxiv2023

The combination of CD49b and CD229 reveals a subset of multipotent cells with short-term activity within the hematopoietic stem cell compartment

Hematopoiesis is maintained by hematopoietic stem cells (HSCs) that replenish all blood lineages throughout life. It is well-established that the HSC pool is functionally heterogeneous consisting of cells differing in longevity, self-renewal ability, cell proliferation, and lineage differentiation. Although HSCs can be identified through the Lineage-Sca-1+c-Kit+CD48-CD34- CD150+ immunophenotype, the cell surface marker combination does not permit absolute purification of functional HSCs with long-term reconstituting ability. Therefore, prospective isolation of long-term HSCs is crucial for mechanistic understanding of the biological functions of HSCs and for resolving functional heterogeneity within the HSC population. Here, we show that the combination of CD229 and CD49b cell surface markers within the phenotypic HSC compartment identifies a subset of multipotent progenitor cells with high proliferative activity and short-term reconstituting ability. Thus, the addition of CD229 and CD49b to conventional HSC markers permits prospective isolation of functional HSCs by distinguishing MPPs in the HSC compartment. SIGNIFICANCE STATEMENTBlood cells are generated by rare stem cells, which based on their defining features of self-renewal and multipotent abilities, are used in transplantation as curative treatment for blood diseases. Despite their clinical importance, mechanisms of stem cell properties are elusive given the inability to isolate pure blood stem cells for prospective analyses. In this study, we demonstrate that stem cells can be isolated by excluding multipotent progenitors, marked by CD229 and CD49b, from the stem cell compartment. Our study has important implications for the analysis of mechanisms regulating stem cell function and is relevant for clinical applications of stem cells.

cell biology↗

bioRxiv2022

FOXO dictates initiation of B cell development and myeloid restriction in common lymphoid progenitors

The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs. SUMMARYCommon lymphoid progenitors co-express the transcription factors FOXO1 and FOXO3. Removing FOXO1 and FOXO3 at this developmental stage results in regained myeloid potential, failed establishment of the early B cell gene regulatory program, and the complete loss of the B cell lineage.

immunology↗