Aplastic Anemia Acquired aplastic anemia (AA) is characterized by aplastic or hypoplastic, fatty marrow, with peripheral pancytopenia of varying degree [83]

Aplastic Anemia Acquired aplastic anemia (AA) is characterized by aplastic or hypoplastic, fatty marrow, with peripheral pancytopenia of varying degree [83]. the marrow, deregulated immune manifestations, all resulting in defective haemopoietic maturation and increased haemopoietic cell apoptosis. Normal haemopoiesis is regulated in the marrow by an extended network of specialized niches, maintaining haemopoietic stem cell (HSC) self-renewal and orchestrating HSC proliferation and differentiation to all blood cell types. Key cellular components of the bone marrow (BM) haemopoietic microenvironment include osteoblasts, sinusoidal endothelial cells, macrophages, adipocytes, and reticular cells, orchestrating the maintenance, proliferation, and differentiation of haemopoietic stem and progenitor cells (HSPCs). Osteoblasts, adipocytes, and reticular cells of the marrow stroma derive from a common progenitor cell, the mesenchymal stem/stromal cell (MSC) [1C5]. Since MSCs and their sulfaisodimidine progeny are among the main components of the marrow stroma, it is reasonable to assume that patient BM MSCs may be partially defective, harboring either native abnormalities and/or secondary defects, due to the long-term exposure to activated marrow components. MSCs could be involved in various pathogenetic mechanisms. MSC haemopoietic supportive capacity, in terms of sulfaisodimidine production of sulfaisodimidine haemopoietic growth factors, or inhibitors, or generation of extracellular matrix, may be defective. MSC differentiation capacity could also indirectly influence haemopoiesis, by controlling marrow cell composition: osteoblasts favor haemopoiesis, yet adipocytes inhibit haemopoiesis. Furthermore MSC immune functions may sulfaisodimidine be deregulated, contributing to the establishment or persistence of the immune-mediated disease manifestations. The purpose of this review is to summarize and discuss literature information regarding the biologic and functional characteristics of BM MSCs in the immune-mediated BMFS, namely, myelodysplastic syndromes, chronic idiopathic neutropenia, and aplastic anemia. 2. BM MSC Properties Mesenchymal stem/stromal MAD-3 Cells (MSCs) are multipotent progenitors able to differentiate into the mesenchymal cell types of adipocytes, chondrocytes, and osteoblasts, additionally showing a wider potency able to differentiate to other cell types, such as myocytes, hepatocytes, or even neurons [3, 6C8]. Originally isolated from the bone marrow [9], MSCs have also been isolated from a variety of other tissues, including dental pulp, bone, lung, adipose tissue, and umbilical cord [10C13]. MSCs have drawn much attention during the last decade in the field of regenerative medicine, mainly due to their capacity to differentiate into specific cell types, their abundant production of soluble growth factors and cytokines, and their immunomodulating properties. As proposed by the International Society for Cellular Therapy three criteria are used to define MSCs: adherence to plastic, specific surface antigen expression, and multipotent differentiation potential (the latter is being tested by cytochemical stains and evaluation of specific gene expression) [14]. Regarding cell immunophenotype, MSCs are positive for CD73, CD90, and CD105 among numerous other cell surface antigens, while being negative for haemopoietic cell markers (such as CD14, CD34, and CD45), class II major histocompatibility complex (HLA-DR), or costimulatory molecules (CD80, CD86) [14]. Due to the absent/low expression of MHC class II molecules, MSCs are immunoprivileged cells and have been used in allo- as well as xenotransplantations. Native BM MSCs are somewhat immunophenotypically different from in vitro expanded cells. Since there is no unique MSC marker, several different cell markers have been used to follow native BM MSCs, such as SSEA4, LNGFR (CD271), or CXCL12 (SDF-1) [15C17]. Evidence suggests that BM MSCs and their progeny are important haemopoietic regulators: osteoprogenitors, osteoblasts, adipocytes, and reticular perivascular cells are all key components of the hematopoietic market [17C19]. The endosteum, comprising of different types of osteolineage cells, takes on a critical part in the maintenance and homing of HSCs. Osteocytes and their part are under investigation. For instance, the CD45?/Ter119?/OPN+ osteoblasts were shown to rapidly expand in vivo, following cyclophosphamide/G-CSF treatment, correlating to HSC proliferation and mobilization, and treated isolated OPN+ cells improved their in vitro haemopoietic supportive ability [20]. The maturation state of osteoblasts appears to be related to the haemopoietic supportive functions, with immature osteoblasts becoming more efficient in HSC support [21]. Adipocytes on the other hand inhibit haemopoiesis, with increased levels of BM adipogenesis inversely correlating to sulfaisodimidine HSC figures [22]. In vivo BM MSCs have been described in close proximity to HSCs, as perivascular CXCL12 abundant reticular (CARs) cells [17, 23, 24] and Nestin+/CD45? cells [25]. The importance of CXCL12-CXCR4 signaling in maintenance and homing of both HSCs and immune cells is definitely.