Abstract
Aplastic anemia (AA) is a heterogeneous disorder of bone marrow failure syndrome. Suggested mechanisms include a primary stem cell deficiency or defect, a secondary stem cell defect due to abnormal regulation between cell death and differentiation, or a deficient microenvironment. In this study, we have tried to investigate the alterations in hematopoietic microenvironment and underlying mechanisms involved in such alterations in an animal model of drug induced AA. We presented the results of studying long term marrow culture, marrow ultra-structure, marrow adherent and hematopoietic progenitor cell colony formation, flowcytometric analysis of marrow stem and stromal progenitor populations and apoptosis mechanism involved in aplastic anemia. The AA marrow showed impairment in cellular proliferation and maturation and failed to generate a functional stromal microenvironment even after 19 days of culture. Ultra-structural analysis showed a degenerated and deformed marrow cellular association in AA. Colony forming units (CFUs) were also severely reduced in AA. Significantly decreased marrow stem and stromal progenitor population with subsequently increased expression levels of both the extracellular and intracellular apoptosis inducer markers in the AA marrow cells essentially pointed towards the defective hematopoiesis; moreover, a deficient and apoptotic microenvironment and the microenvironmental components might have played the important role in the possible pathogenesis of AA.
Highlights
Aplastic anemia (AA) is an acquired disease characterized by an extremely hypocellular marrow and peripheral blood pancytopenia due to chronic depression of hematopoiesis in the bone marrow [1,2,3]
The exact causes and mechanisms involved in the bone marrow failure in aplastic anemia is still not quite steadily explained; it is clear that acquired aplastic anemia is a heterogeneous disease caused by different pathophysiological conditions [4, 5]
The possible pathophysiological conditions that account for AA include decreased hematopoietic stem cell (HSC) number, impaired hematopoietic stem cell function, and increased bone marrow cellular apoptosis level and the functional and structural defects in the bone marrow hematopoietic microenvironment and several microenvironmental components [6,7,8,9]
Summary
Aplastic anemia (AA) is an acquired disease characterized by an extremely hypocellular marrow and peripheral blood pancytopenia due to chronic depression of hematopoiesis in the bone marrow [1,2,3]. The exact causes and mechanisms involved in the bone marrow failure in aplastic anemia is still not quite steadily explained; it is clear that acquired aplastic anemia is a heterogeneous disease caused by different pathophysiological conditions [4, 5]. The possible pathophysiological conditions that account for AA include decreased hematopoietic stem cell (HSC) number, impaired hematopoietic stem cell function, and increased bone marrow cellular apoptosis level and the functional and structural defects in the bone marrow hematopoietic microenvironment and several microenvironmental components [6,7,8,9]. Within the marrow cavity the mystery of stem/progenitor cell health has been found to be critically dependent on microenvironmental components which are of varied and diverse nature [11,12,13]. Recent studies have revealed that the hematopoietic bone marrow microenvironment is heterogeneous in respect to bone lining osteoblasts, fibroblasts, multilaminar and branched stromal barrier cells, and the reticuloendothelial
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