Alterations in Hematopoietic Microenvironment in Patients with Aplastic Anemia

Abstract

Mechanisms of hematopoietic failure in patients with aplastic anemia (AA) are obscure. We investigate alterations in the hematopoietic microenvironment in AA patients. We present the results of studying mesenchymal stromal cells (MSC), fibroblastic colony-forming units (CFU-F), and adherent cell layers (ACL) of long-term bone marrow cultures (LTBMC) from bone marrow (BM) samples of AA patients. MSC of AA patients proliferated longer than those of donors. In half of the patients' MSC cultures, adipogenesis was impaired. Osteogenic differentiation was not achieved in 36% of AA MSC. CFU-F formed enlarged colonies, and their concentration in the BM of AA patients was significantly increased. Our data suggest that the physiological activation of the stromal microenvironment is characteristic of AA. We detected a decrease in the expression of the angiopoetin-1 (ANG-1) and vascular cell adhesion molecule-1 (VCAM-1) genes, together with an increase in the expression of vascular endothelial growth factor (VEGF) in ACL of AA patients. This indicates abnormal regulatory patterns in both osteoblastic and vascular contexts. Addition of AA patients' serum to donors' LTBMC for 3 weeks induced similar gene expression alterations. The addition of parathyroid hormone (PTH) resulted in the expression levels of analyzed genes returning to normal, in both AA LTBMC and donor cultures treated with AA serum. The physiologic status of the BM stromal microenvironment (MSC, CFU-F, and ACL of LTBMC) of AA patients was altered.

The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells

“…Such a response could be delayed rather than direct. Similar changes were found in patients with aplastic anemia, whose stromal cells were more active than the donor cells .…”

Levamisole suppresses adipogenesis of aplastic anaemia‐derived bone marrow mesenchymal stem cells through ZFP36L1‐PPARGC1B axis

“…Previous studies have suggested that BM adipocytes are predominantly negative regulators of the BM microenvironment and are less supportive to hematopoiesis than those of other cell types derived from MSCs, such as osteoblasts . The BM of AA patients often exhibits increasing adipocytes and decreasing osteoblasts, which may be causatively associated with the abnormal hematopoietic niche and impaired hematopoiesis. Here in this study, we confirmed that AA BM‐MSCs are more susceptible to be induced into adipogenic differentiation compared with control BM‐MSCs, which, to some extent, accounts for the fatty phenomenon and defective hematopoiesis in AA marrow.…”

“…Aplastic anaemia (AA) is a rare and life‐threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with fatty bone marrow (BM) . The pathogenic factors causally associated with AA may include immune abnormality, quantitative and qualitative defects in hematopoietic stem/progenitors cells and altered marrow microenvironment . Bone marrow mesenchymal stem cells (MSCs) can differentiate into osteoblast, adipocytes and chondrocytes, which together constitute the major cellular components of BM microenvironment providing critical support for hematopoiesis .…”

Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

“…It affects mostly children, young adults, and adults, over 60 years of age [17]. This condition can be similar to other hematologic disorders, however, in most cases, the AA is caused by reduced HSCs function, an increase in HSCs apoptosis level, consequently, the decreased of HSCs and hematopoietic progenitors and lastly, microenvironment fat replacement [18,19].…”