Abstract
BackgroundDissection of mechanisms involved in the regulation of bone marrow microenvironment through cell–cell and cell–matrix contacts is essential for the detailed understanding of processes underlying bone marrow activities both under physiological conditions and in hematologic malignancies. Here we describe Emilin-2 as an abundant extracellular matrix component of bone marrow stroma.MethodsImmunodetection of Emilin-2 was performed in bone marrow sections of mice from 30 days to 6 months of age. Emilin-2 expression was monitored in vitro in primary and mesenchymal stem cell lines under undifferentiated and adipogenic conditions. Hematopoietic stem cells and progenitors in bone marrow of 3- to 10-month-old wild-type and Emilin-2 null mice were analyzed by flow cytometry.ResultsEmilin-2 is deposited in bone marrow extracellular matrix in an age-dependent manner, forming a meshwork that extends from compact bone boundaries to the central trabecular regions. Emilin-2 is expressed and secreted by both primary and immortalized bone marrow mesenchymal stem cells, exerting an inhibitory action in adipogenic differentiation. In vivo Emilin-2 deficiency impairs the frequency of hematopoietic stem/progenitor cells in bone marrow during aging.ConclusionOur data provide new insights in the contribution of bone marrow extracellular matrix microenvironment in the regulation of stem cell niches and hematopoietic progenitor differentiation.
Highlights
Bone marrow (BM) is a heterogeneous tissue involved in hematopoiesis
Studies aimed at the characterization of hematopoietic stem and progenitor cell populations in myelodysplastic syndromes (MDS) patients correlating with the risk of acute myeloid leukemia (AML) revealed an increased number of hematopoietic stem cells (HSC) and common myeloid progenitors (CMP) coupled with a decreased amount of granulocyte myeloid progenitors (GMP) in MDS with low risk of AML, whereas an expansion of GMP was observed in patients with high risk of AML onset [10,11,12]
Emilin-2 deposition in BM-extracellular matrix (ECM) increased during postnatal life, as shown by staining at 1, 3 and 6 months (Fig. 1B, E, H),forming a meshwork that partially co-localized with Collagen IV, a well characterized BMECM protein, and surrounding various sets of cells (Fig. 1C, F, I)
Summary
Bone marrow (BM) is a heterogeneous tissue involved in hematopoiesis. hematopoietic stem cells (HSC) exert the main role in repopulating immune cells and all blood lineages, their activity can be modulatedDa Ros et al Stem Cell Research & Therapy (2022) 13:2The importance of MSC in the maintenance of BM homeostasis is further highlighted by several pathological conditions in which these cells can be modulated by tumor cells, like multiple myeloma or leukemia cells, to mold a tumor-supporting microenvironment through secretion of exosomes and matrix metalloproteinases or modification of osteogenic/adipogenic potential [6,7,8]. Alterations of BM microenvironment occur in multiple myeloma and leukemia, and in myelodysplastic syndromes (MDS), a heterogeneous group of disorders characterized by anomalous growth of HSC and their abnormal differentiation in hematopoietic progenitor cells (HPC) as common myeloid progenitors (CMP), granulocyte myeloid progenitors (GMP) and megakaryocyte–erythrocyte progenitors (MEP) [9]. Studies aimed at the characterization of hematopoietic stem and progenitor cell populations in MDS patients correlating with the risk of acute myeloid leukemia (AML) revealed an increased number of HSC and CMP coupled with a decreased amount of GMP in MDS with low risk of AML, whereas an expansion of GMP was observed in patients with high risk of AML onset [10,11,12]. Recent studies of the matrisome [21] of AML patients highlighted a number of ECM-related genes with potential involvement in tumor onset and progression [22, 23]. We describe Emilin-2 as an abundant extracellular matrix component of bone marrow stroma
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