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.

Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34+ hematopoietic stem and progenitor cells

“…BM‐MSC are an essential component of the BM microenvironment and are pivotal for the balanced regulation of HSPC functions (Jing et al, 2010; Méndez‐Ferrer et al, 2010; Saleh et al, 2015; Walenda et al, 2010). We and a few other studies have reported morphologic, genetic and functional impairment of BM‐MSC in acquired AA (Chaturvedi et al, 2018; Hamzic et al, 2015; Huo et al, 2020; Li et al, 2012; Shipounova et al, 2009; Tripathy et al, 2014). Another report shows that BM‐MSC of AA patients when cocultured with CD34 + cells, reduced the proliferative and clonogenic potential of CD34 + cells (Hamzic et al, 2015).…”

Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease

“…46 Our data are in partial disagreement with those of other studies suggesting that AA BM-MSC are aberrant. 8,41,42,44,46,48 From a methodological point of view, we assessed the features of AA BM-MSC beyond morphology, gene expression, differentiation potential and proliferation by analyzing the cells' ability to support hematopoiesis in vitro and in vivo and their immune properties. Biologically, all our patients, but one, were elderly patients while other studies focused on chil-BM-MSC in aplastic anemia haematologica | 2014; 99(7) dren/young adults with AA.…”

“…8,[41][42][43][44][45][46][47][48] These studies mainly claim that AA BM-MSC have aberrant morphology, impaired adipogenic and osteogenic potential, changes in gene expression, and a reduced ability to support hematopoiesis in vitro. However, to the best of our knowledge, no study so far has prospectively addressed in depth the ability of AA BM-MSC to maintain hematopoietic homeostasis and progenitor function in vitro, their in vivo repopulating function in xenotransplant models, or the immunosuppressive and anti-inflammatory properties on these cells.…”

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

“…32,34 The proliferative and clonogenic capacity of mesenchymal cells (an important immune regulator) in the marrow microenvironment has been reported to be diminished in AA. [46][47][48][49] However, these findings have not been consistent. 50 Nevertheless, an impaired microenvironment could contribute to pathogenesis, limiting support for haematopoiesis and lack of regulatory signals.…”