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      Bone marrow Tregs mediate stromal cell function and support hematopoiesis via IL-10

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          Abstract

          The nonimmune roles of Tregs have been described in various tissues, including the BM. In this study, we comprehensively phenotyped marrow Tregs, elucidating their key features and tissue-specific functions. We show that marrow Tregs are migratory and home back to the marrow. For trafficking, marrow Tregs use S1P gradients, and disruption of this axis allows for specific targeting of the marrow Treg pool. Following Treg depletion, the function and phenotype of both mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) was impaired. Transplantation also revealed that a Treg-depleted niche has a reduced capacity to support hematopoiesis. Finally, we found that marrow Tregs are high producers of IL-10 and that Treg-secreted IL-10 has direct effects on MSC function. This is the first report to our knowledge revealing that Treg-secreted IL-10 is necessary for stromal cell maintenance, and our work outlines an alternative mechanism by which this cytokine regulates hematopoiesis.

          Abstract

          Bone marrow Tregs regulate stromal cell function to maintain hematopoiesis through IL-10 and provide a potential therapeutic avenue for stromal manipulation.

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          Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris

          (2018)
          We have created a compendium of single cell transcriptomic data from the model organism Mus musculus comprising more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations, and allow for direct and controlled comparison of gene expression in cell types shared between tissues, such as T-lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3’-end counting, enabled the survey of thousands of cells at relatively low coverage, while the other, FACS-based full length transcript analysis, enabled characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.
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            Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.

            Simón Méndez-Ferrer, Tatyana Michurina, Francesca Ferraro … (2010)
            The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
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              The bone marrow niche for haematopoietic stem cells.

              Sean Morrison, David Scadden (2014)
              Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
              Article 0 comments Cited 415 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Virginia Camacho:
                ORCID: http://orcid.org/0000-0002-6970-0932
                Zhengqin Yang
                James F. George:
                ORCID: http://orcid.org/0000-0003-0325-7891
                Henry Yang
                Craig L. Maynard:
                ORCID: http://orcid.org/0000-0001-5876-8168
                Casey T. Weaver:
                ORCID: http://orcid.org/0000-0002-2180-1793
                Robert S. Welner
                Journal
                Journal ID (nlm-ta): JCI Insight
                Journal ID (iso-abbrev): JCI Insight
                Journal ID (publisher-id): JCI Insight
                Title: JCI Insight
                Publisher: American Society for Clinical Investigation
                ISSN (Electronic): 2379-3708
                Publication date (Electronic, pub): 19 November 2020
                Publication date (Electronic, collection): 19 November 2020
                Publication date PMC-release: 19 November 2020
                Volume: 5
                Issue: 22
                Electronic Location Identifier: e135681
                Affiliations
                [1 ]Division of Hematology-Oncology,
                [2 ]Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, and
                [3 ]Division of Cardiothoracic Surgery, Department of Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
                [4 ]Cancer Science Institute of Singapore & Department of Biochemistry, National University of Singapore, Singapore.
                [5 ]Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
                [6 ]Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
                [7 ]Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
                [8 ]Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
                Author notes
                Address correspondence to Robert S. Welner, 1824 6th Ave. S., WTI 510D, Birmingham, Alabama 35233, USA. Phone: 205.975.3960; Email: rwelner@ 123456uab.edu .
                Author information
                http://orcid.org/0000-0002-6970-0932
                http://orcid.org/0000-0003-0325-7891
                http://orcid.org/0000-0001-5876-8168
                http://orcid.org/0000-0002-2180-1793
                Article
                Publisher ID: 135681
                DOI: 10.1172/jci.insight.135681
                PMC ID: 7710301
                PubMed ID: 33208555
                SO-VID: e87bd603-fbf5-4fee-ac22-67c31b2aa033
                Copyright © © 2020 Camacho et al.
                License:

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 13 December 2019
                Date accepted : 7 October 2020
                Funding
                Funded by: National Heart, Lung, and Blood Institute, https://doi.org/10.13039/100000050;
                Award ID: HL131477
                Funded by: NIH Immunology T32 Training Grant
                Award ID: 2T32AI007051
                Funded by: ASH Bridge Funding
                Award ID: 2018
                Categories
                Subject: Research Article

                Keywords: hematology,immunology,bone marrow,hematopoietic stem cells,t cells
                Data availability:
                Keywords: hematology, immunology, bone marrow, hematopoietic stem cells, t cells

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