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      Mesenchymal stromal cells (MSCs) induce ex vivo proliferation and erythroid commitment of cord blood haematopoietic stem cells (CB-CD34+ cells)

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          Abstract

          A human bone marrow-derived mesenchymal stromal cell (MSCs) and cord blood-derived CD34+ stem cell co-culture system was set up in order to evaluate the proliferative and differentiative effects induced by MSCs on CD34+ stem cells, and the reciprocal influences on gene expression profiles. After 10 days of co-culture, non-adherent (SN-fraction) and adherent (AD-fraction) CD34+ stem cells were collected and analysed separately. In the presence of MSCs, a significant increase in CD34+ cell number was observed (fold increase = 14.68), mostly in the SN-fraction (fold increase = 13.20). This was combined with a significant increase in CD34+ cell differentiation towards the BFU-E colonies and with a decrease in the CFU-GM. These observations were confirmed by microarray analysis. Through gene set enrichment analysis (GSEA), we noted a significant enrichment in genes involved in heme metabolism (e.g. LAMP2, CLCN3, BMP2K), mitotic spindle formation and proliferation (e.g. PALLD, SOS1, CCNA1) and TGF-beta signalling (e.g. ID1) and a down-modulation of genes participating in myeloid and lymphoid differentiation (e.g. PCGF2) in the co-cultured CD34+ stem cells. On the other hand, a significant enrichment in genes involved in oxygen-level response (e.g. TNFAIP3, SLC2A3, KLF6) and angiogenesis (e.g. VEGFA, IGF1, ID1) was found in the co-cultured MSCs. Taken together, our results suggest that MSCs can exert a priming effect on CD34+ stem cells, regulating their proliferation and erythroid differentiation. In turn, CD34+ stem cells seem to be able to polarise the BM-niche towards the vascular compartment by modulating molecular pathways related to hypoxia and angiogenesis.

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          "Mesenchymal" stem cells.

          Two opposing descriptions of so-called mesenchymal stem cells (MSCs) exist at this time. One sees MSCs as the postnatal, self-renewing, and multipotent stem cells for the skeleton. This cell coincides with a specific type of bone marrow perivascular cell. In skeletal physiology, this skeletal stem cell is pivotal to the growth and lifelong turnover of bone and to its native regeneration capacity. In hematopoietic physiology, its role as a key player in maintaining hematopoietic stem cells in their niche and in regulating the hematopoietic microenvironment is emerging. In the alternative description, MSCs are ubiquitous in connective tissues and are defined by in vitro characteristics and by their use in therapy, which rests on their ability to modulate the function of host tissues rather than on stem cell properties. Here, I discuss how the two views developed, conceptually and experimentally, and attempt to clarify the confusion arising from their collision.
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            Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine.

            Mesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
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              Making sense of hematopoietic stem cell niches.

              The hematopoietic stem cell (HSC) niche commonly refers to the pairing of hematopoietic and mesenchymal cell populations that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the developmental stage that allows proliferating HSCs to expand before they reach the bone marrow where they adopt a quiescent phenotype that protects their integrity and functions. Recent studies have sought to clarify the complexity behind the HSC niche by assessing the contributions of specific cell populations to HSC maintenance. In particular, perivascular microenvironments in the bone marrow confer distinct vascular niches that regulate HSC quiescence and the supply of lineage-committed progenitors. Here, we review recent data on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 February 2017
                2017
                : 12
                : 2
                : e0172430
                Affiliations
                [1 ]Unit of Blood Diseases and Stem Cells Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy
                [2 ]Laboratorio CREA (Centro di Ricerca Emato-oncologica AIL), ASST Spedali Civili of Brescia, Brescia, Italy
                [3 ]Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
                [4 ]Section of Genomics and Personalized Medicine, Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy
                [5 ]Parco Scientifico e Tecnologico Materiali Innovativi e Ricerca Applicata del Mirandolese, Modena, Italy
                [6 ]Applied Research on Cancer-Network (ARC-NET), University of Verona, Verona, Italy
                [7 ]Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy
                [8 ]Unit of Biology and Genetics, Department of Molecular and Translational Medicine (DMTM), University of Brescia, Brescia, Italy
                [9 ]U.O. of Obstetrics and Gynecology I, ASST Spedali Civili di Brescia, Brescia, Italy
                [10 ]Centro di Ricerche Genomiche, Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
                [11 ]Interdepartmental Laboratory of Medical Research (LURM), University of Verona, Verona, Italy
                [12 ]Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation and Cryopreservation, ASST Spedali Civili di Brescia, Brescia, Italy
                [13 ]Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
                Instituto Butantan, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: SF DR.

                • Data curation: FC VC.

                • Formal analysis: SP ADP PPP EG G. Borsani ET MTS SB CZ MK CA DR.

                • Funding acquisition: DR.

                • Investigation: SP ADP CG EZ G. Bassi.

                • Methodology: SP ADP.

                • Project administration: DR.

                • Resources: CG EZ G. Bassi AL ET MTS M. Malagola MK M. Marini CA SF DR.

                • Supervision: DR.

                • Visualization: SP ADP.

                • Writing – original draft: SP ADP.

                • Writing – review & editing: PPP MK SF DR.

                Article
                PONE-D-16-42783
                10.1371/journal.pone.0172430
                5322933
                28231331
                207db96b-95f6-4cc5-89e4-38f4f5876146
                © 2017 Perucca et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 October 2016
                : 3 February 2017
                Page count
                Figures: 7, Tables: 0, Pages: 19
                Funding
                This study was supported by PRIN_2009, BCC “Pompiano e Franciacorta”, LIONS Bassa Bresciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Stem Cells
                Mesenchymal Stem Cells
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Developmental Biology
                Cell Differentiation
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Stem Cells
                Hematopoietic Stem Cells
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Microarrays
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Stem Cells
                Medicine and Health Sciences
                Hematology
                Hematopoiesis
                Custom metadata
                The complete dataset has been submitted to the gene expression omnibus data (GEO) public database at NCBI, and the accession number is GSE90970.

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                Uncategorized

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