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Mobilized Multipotent Hematopoietic Progenitors Stabilize and Expand Regulatory T Cells to Protect Against Autoimmune Encephalomyelitis

ABSTRACT: Achieving immunoregulation via in vivo expansion of Foxp3+ regulatory CD4+ T cells (Treg) remains challenging. We have shown that mobilization confers to multipotent hematopoietic progenitors (MPPs) the capacity to enhance Treg proliferation. Transcriptomic analysis of Tregs co-cultured with MPPs revealed enhanced expression of genes stabilizing the suppressive function of Tregs as well as the activation of IL-1?–driven pathways. Adoptive transfer of only 25,000 MPPs effectively reduced the development of experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for multiple sclerosis (MS). Production of the pathogenic cytokines IL-17 and GM-CSF by spinal cord-derived CD4+ T-cells in MPP-protected recipients was reduced while Treg expansion was enhanced. Treg depletion once protection by MPPs was established, triggered disease relapse to the same level as in EAE mice without MPP injection. The key role of IL-1? was further confirmed in vivo by the lack of protection against EAE in recipients of IL-1?–deficient MPPs. Mobilized MPPs may thus be worth considering for cell therapy of MS either per se or for enrichment of HSC grafts in autologous bone marrow transplantation already implemented in patients with severe refractory multiple sclerosis.

SUBMITTER: Korniotis S

PROVIDER: S-EPMC7786289 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mobilized multipotent hematopoietic progenitors stabilize and expand regulatory T-cells

Project description:Objective: Achieving immunoregulation via in vivo expansion of Foxp3+ regulatory CD4+ T cells (Treg) remains challenging. Considerable efforts are being produced aiming at promoting expansion of Tregs in vitro with IL-2, rapamycin, activation with anti-CD3/CD28 mAb-coated beads or with minute foreign antigen doses, for subsequent administration to patients with autoimmune and alloimmune diseases. We have previously shown that mobilized multipotent hematopoietic progenitors (MPPs)collected in peripheral blood stem cell grafts, have the capacity to enhance Treg proliferation in vivo. Design: To analyze the possible mechanisms involved in mouse CD4+CD25high regulatory T-cells (Treg cells) expansion promoted by mobilized MPPs (MPPs), we sequenced and compared the transcriptome of activated Treg extracted from simple culture or from co-culture with MPPs. Results: Tregs cultivated with mobilized MPP had a specialized profile, with enhanced expression of sets of genes coding for receptors and transcription factors that stabilize their regulatory function particularly in inflammatory settings including CD4, CD25 (Il2ra), Foxp3, CD127low (Il7ralpha), Ctla4 high, Tnfrsf18 (Gitr) high, Ikzf2 (Helios) high, Tnfrsf4 (Ox40/CD134) high, Itgae (CD103), regulated by Satb1, Runx, Gata3. Moreover, they exhibit enhanced expression of Prdm1, recently reported to prevent methylation of Foxp3 within Tregs in central nervous system inflammation (14), and Nr4a, that stabilizes Tregs against their differentiation into effector T-cells (15). Their survival is improved by a reduced apoptosis controlled by reduced Tnfrsf1b (p75, Tnfr2) signaling pathway and FOXO-mediated transcription. Their cell cycle is arrested at the G1 stage through enhanced Cdkn1a (p21) and regulated by Runx3 and p53. conclusion: Tregs interacting with mobilized MPP are shaped, stabilized with high immunosuppressive properties.

2020-12-18 | GSE155148 | GEO

Mobilized multipotent hematopoietic progenitors stabilize and expand regulatory T-cells

Project description:Mobilized multipotent hematopoietic progenitors stabilize and expand regulatory T-cells

| PRJNA648850 | ENA

Mobilized Multipotent Hematopoietic Progenitors Promote Expansion and Survival of Allogeneic Tregs and Protect Against Graft Versus Host Disease.

Project description:Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) is routinely performed with peripheral blood stem cells (PBSCs) mobilized by injection of G-CSF, a growth factor which not only modulates normal hematopoiesis but also induces diverse immature regulatory cells. Based on our previous evidence that G-CSF-mobilized multipotent hematopoietic progenitors (MPP) can increase survival and proliferation of natural regulatory T cells (Tregs) in autoimmune disorders, we addressed the question how these cells come into play in mice and humans in an alloimmune setting. Using a C57BL/6 mouse model, we demonstrate that mobilized MPP enhance the immunosuppressant effect exerted by Tregs, against alloreactive T lymphocytes, both in vitro and in vivo. They do so by migrating to sites of allopriming, interacting with donor Tregs and increasing their numbers, thus reducing the lethality of graft-versus-host disease (GVHD). Protection correlates likewise with increased allospecific Treg counts. Furthermore, we provide evidence for a phenotypically similar MPP population in humans, where it shares the capacity to promote selective Treg expansion in vitro. We postulate that G-CSF-mobilized MPPs might become a valuable cellular therapy to expand donor Tregs in vivo and prevent GVHD, thereby making allo-HSCT safer for the treatment of leukemia patients.

| S-EPMC7907505 | biostudies-literature

Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells.

Project description:The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases.

| S-EPMC4942579 | biostudies-literature

Asymmetrical lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors.

Project description:The mechanism of lineage commitment from hematopoietic stem cells (HSCs) is not well understood. Although commitment to either the lymphoid or the myeloid lineage is popularly viewed as the first step of lineage restriction from HSCs, this model of hematopoietic differentiation has recently been challenged. The previous identification of multipotent progenitors (MPPs) that can produce lymphocytes and granulocyte/macrophages (GMs) but lacks erythroid differentiation ability suggests the existence of an alternative HSC differentiation program. Contribution to different hematopoietic lineages by these MPPs under physiological conditions, however, has not been carefully examined. In this study, we performed a refined characterization of MPPs by subfractionating three distinct subsets based on Flt3 and vascular cell adhesion molecule 1 expression. These MPP subsets differ in their ability to give rise to erythroid and GM lineage cells but are equally potent in lymphoid lineage differentiation in vivo. The developmental hierarchy of these MPP subsets demonstrates the sequential loss of erythroid and then GM differentiation potential during early hematopoiesis. Our results suggest that the first step of lineage commitment from HSCs is not simply a selection between the lymphoid and the myeloid lineage.

| S-EPMC2118384 | biostudies-other

Multipotent hematopoietic progenitors divide asymmetrically to create progenitors of the lymphomyeloid and erythromyeloid lineages.

Project description:Hematopoietic stem and progenitor cells (HSPCs) can self-renew and create committed progenitors, a process supposed to involve asymmetric cell divisions (ACDs). Previously, we had linked the kinetics of CD133 expression with ACDs but failed to detect asymmetric segregation of classical CD133 epitopes on fixed, mitotic HSPCs. Now, by using a novel anti-CD133 antibody (HC7), we confirmed the occurrence of asymmetric CD133 segregation on paraformaldehyde-fixed and living HSPCs. After showing that HC7 binding does not recognizably affect biological features of human HSPCs, we studied ACDs in different HSPC subtypes and determined the developmental potential of arising daughter cells at the single-cell level. Approximately 70% of the HSPCs of the multipotent progenitor (MPP) fraction studied performed ACDs, and about 25% generated lymphoid-primed multipotent progenitor (LMPP) as wells as erythromyeloid progenitor (EMP) daughter cells. Since MPPs hardly created daughter cells maintaining MPP characteristics, our data suggest that under conventional culture conditions, ACDs are lineage instructive rather than self-renewing.

| S-EPMC4263999 | biostudies-literature

A20 deficiency in multipotent progenitors perturbs quiescence of hematopoietic stem cells.

Project description:Inflammatory signals have been shown to play a critical role in controlling the maintenance and functions of hematopoietic stem cells (HSCs). While the significance of inflammation in hematopoiesis has begun to unfold, molecular mechanisms and players that govern this mode of HSC regulation remain largely unknown. The E3 ubiquitin ligase A20 has been considered as a central gatekeeper of inflammation. Here, we have specifically depleted A20 in multi-potent progenitors (MPPs) and studied its impact on hematopoiesis. Our data suggest that lack of A20 in Flt3+ progenitors causes modest alterations in hematopoietic differentiation. Analysis of hematopoietic stem and progenitor cell (HSPC) pool revealed alterations in HSPC subsets including, HSCs, MPP1, MPP2, MPP3 and MPP4. Interestingly, A20 deficiency in MPPs caused loss of HSC quiescence and compromised long-term hematopoietic reconstitution. Mechanistic studies identified that A20 deficiency caused elevated levels of Interferon-γ signaling and downregulation of p57 in HSCs. In essence, these studies identified A20 as a key regulator of HSC quiescence and cell fate decisions.

| S-EPMC6919550 | biostudies-literature

Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood.

Project description:Mouse hematopoiesis is initiated by long-term hematopoietic stem cells (HSC) that differentiate into a series of multipotent progenitors that exhibit progressively diminished self-renewal ability. In human hematopoiesis, populations enriched for HSC activity have been identified, as have downstream lineage-committed progenitors, but multipotent progenitor activity has not been uniquely isolated. Previous reports indicate that human HSC are enriched in Lin-CD34+CD38- cord blood and bone marrow and express CD90. We demonstrate that the Lin-CD34+CD38- fraction of cord blood and bone marrow can be subdivided into three subpopulations: CD90+CD45RA-, CD90-CD45RA-, and CD90-CD45RA+. Utilizing in vivo transplantation studies and complementary in vitro assays, we demonstrate that the Lin-CD34+CD38-CD90+CD45RA- cord blood fraction contains HSC and isolate this activity to as few as 10 purified cells. Furthermore, we report the first prospective isolation of a population of candidate human multipotent progenitors, Lin-CD34+CD38-CD90-CD45RA- cord blood.

| S-EPMC2292126 | biostudies-other

Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging.

Project description:Declining immune function with age is associated with reduced lymphoid output of hematopoietic stem cells (HSCs). Currently, there is poor understanding of changes with age in the heterogeneous multipotent progenitor (MPP) cell compartment, which is long lived and responsible for dynamically regulating output of mature hematopoietic cells. In this study, we observe an early and progressive loss of lymphoid-primed MPP cells (LMPP/MPP4) with aging, concomitant with expansion of HSCs. Transcriptome and in vitro functional analyses at the single-cell level reveal a concurrent increase in cycling of aging LMPP/MPP4 with loss of lymphoid priming and differentiation potential. Impaired lymphoid differentiation potential of aged LMPP/MPP4 is not rescued by transplantation into a young bone marrow microenvironment, demonstrating cell-autonomous changes in the MPP compartment with aging. These results pinpoint an age and cellular compartment to focus further interrogation of the drivers of lymphoid cell loss with aging.

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Lineage-specific activators affect beta-globin locus chromatin in multipotent hematopoietic progenitors.

Project description:During development, the regulated expression of tissue-specific genes can be preceded by their potentiation, that is, by chromatin activation in progenitor cells. For example, the human beta-like globin genes are potentiated in a gene- and developmental-specific manner in hematopoietic progenitors. Developmental regulation of human beta-gene expression in erythroid cells is mostly determined by transcriptional activators; however, it is not clear how gene-specific potentiation is set in hematopoietic progenitors. Using human and transgenic multipotent hematopoietic progenitors, we demonstrate that human beta-globin locus activation is characterized by TBP, NF-E2, CBP and BRG1 recruitment at both the Locus Control Region and human beta-gene promoter. Our results further indicate that in hematopoietic progenitors, EKLF influences chromatin organization at the human beta-globin locus and is instrumental for human beta-gene potentiation. Thus, we show that lineage-specific transcriptional activators expressed at basal levels in progenitor cells can participate in gene potentiation.

| S-EPMC1538551 | biostudies-literature

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