Microenvironmental Effect on Red Cell Generation in MDS
Abstract
Bone marrow (BM) is the vital site where hematopoietic stem cells (HSCs) are maintained and all blood is produced. Bone marrow failure (BMF) occurs when HSCs in the BM fail to generate enough healthy blood cells, including red blood cells (RBCs), platelets, and white blood cells. Myelodysplastic syndromes (MDS) are common BMF diseases, caused by accumulation of genetic and epigenetic aberrations. The primary disorder can be inherited or acquired after birth (non-inherited), and symptoms gets exacerbated when further acquired aberrations accumulate. The incidence of MDS is higher in aging populations. In addition to lifestyle-related risk factors such as smoking, exposure to pesticides and mutagenic chemicals, and exposure to extra doses of radiation, such as with atomic bomb survivors, nuclear power plant accidents, and cancer treatments with chemotherapy or radiotherapy, increases the incidence of MDS significantly. RBCs (erythrocytes), the most abundant cell type in peripheral blood, are produced in adult BM through a process termed erythropoiesis. Anemia, a symptom of lacking functional RBCs, is the predominant clinical manifestation of MDS, which correlates with abnormal RBC production due to dysplastic erythropoiesis. Erythropoiesis is a complex procedure including multiple stages: (1) HSCs differentiated to common myeloid progenitors (CMPs); (2) CMPs further committed to lineage-restricted early erythroid progenitors (proerythroblasts or pronormoblasts); (3) pronormoblast maturation to give rise to basophilic erythroblasts, then polychromatic erythroblasts, and then orthochromatic erythroblasts; (4) terminal differentiation emerged as mature enucleated erythrocytes (reticulocyte) after expelling the nucleus. It is noteworthy that the tightly regulated process of erythropoiesis also requires crosstalk from BM microenvironment networks, and the dysplastic erythropoiesis could occur at any stage. Recent identification of genetic and epigenetic alterations in patients of MDS, studies of animal models, and studies of in vitro abnormality of MDS patient-derived cells have advanced our understanding on the etiology of MDS and strongly suggest the key role of the BM microenvironment in MDS manifestation and progress. However, in many cases, the evidence is controversial, perhaps because of the heterogeneous nature of MDS diseases, the complexity of erythropoiesis and inconsistency in study systems, which together makes interpretation challenging. The molecular pathogenesis of dysplastic erythropoiesis is largely unknown, partially due to a lack of experimental system to study a stage-specific erythropoiesis. It is also unclear on how the microenvironment contributes to dysplastic erythropoiesis. The goal of this project is to investigate intrinsic defects of erythropoiesis from HSPCs and extrinsic defects of microenvironments as well as the convergent effect of the two that impair erythropoiesis in MDS by using a controllable and reliable experimental system that partially recapitulate the BM cellular niches. We have recently developed a system to mimic cellular niches in BM microenvironments for promoting erythropoiesis from human pluripotent stem cells. By using the two-step niche system composed of endothelial cells and bone marrow stromal cells, we were able to efficiently generate enucleated erythrocytes from stem cells, demonstrating that our system is valid to reconstitute the function of nature BM microenvironment in supporting erythropoiesis. We would use this relative simple system as an erythropoiesis platform to investigate the diverse mechanisms of pathogenesis of dysplastic erythropoiesis of MDS. The advantage of our proposed approach is derived in the consistency and flexibility of the system, as well as its accessibility to a broad range of analysis methods. We will test the hypothesis that diverse cellular niche cues play distinct roles in regulating the development of erythroblasts and the generation of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010812
Entities
People
- Zack Wang
Organizations
- Johns Hopkins University
- United States Army