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Tcf12 balances the reconstitution and differentiation capacity of hematopoietic stem cell.

ABSTRACT: Tcf12 has been identified as one of the main helix-loop-helix transcription factors that regulates T cell development from double negative to double positive stage transition. While, the function of Tcf12 in hematopoietic stem cells remains not investigated. In this study, we observed that Tcf12 is expressed in HSCs and targeted deletion of Tcf12 in hematopoietic cells results in increased frequency and absolute number of HSCs, but compromises the reconstitution capacity of HSCs. Further analysis reveals that Tcf12 is dispensable for the self-renewal of HSCs. The declined reconstituted capacity of Tcf12^-/- HSCs stems from the decrease in the ability to differentiate into lymphoid-primed multipotent progenitors, and furthermore B and T lineages.

SUBMITTER: Liao M

PROVIDER: S-EPMC8974954 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Tcf12 balances the reconstitution and differentiation capacity of hematopoietic stem cell.

Liao Min M Wang Jianwei J

Blood science (Baltimore, Md.) 20201201 1

Tcf12 has been identified as one of the main helix-loop-helix transcription factors that regulates T cell development from double negative to double positive stage transition. While, the function of Tcf12 in hematopoietic stem cells remains not investigated. In this study, we observed that Tcf12 is expressed in HSCs and targeted deletion of Tcf12 in hematopoietic cells results in increased frequency and absolute number of HSCs, but compromises the reconstitution capacity of HSCs. Further analysi ...[more]

PMID: 35399207

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Project description:Background and objectivesAutologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.MethodsUsing longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.ResultsTotal B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.DiscussionOur detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

Dataset Information

Tcf12 balances the reconstitution and differentiation capacity of hematopoietic stem cell.

Publications

Tcf12 balances the reconstitution and differentiation capacity of hematopoietic stem cell.

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