Abstract
Gelsolin, an actin-remodeling protein, is involved in cell motility, cytoskeletal remodeling, and cytokinesis and is abnormally expressed in many cancers. Recently, human recombinant plasma gelsolin protein (pGSN) was reported to have important roles in cell cycle and maturation of primary erythroblasts. However, the role of human plasma gelsolin in late stage erythroblasts prior to enucleation and putative clinical relevance in patients with myelodysplastic syndrome (MDS) and hemato-oncologic diseases have not been reported. Polychromatic and orthochromatic erythroblasts differentiated from human cord blood CD34+ cells, and human bone marrow (BM) cells derived from patients with MDS, were cultured in serum-free medium containing pGSN. Effects of pGSN on mitochondria, erythroid dysplasia, and enucleation were assessed in cellular and transcriptional levels. With pGSN treatment, terminal maturation at the stage of poly- and ortho-chromatic erythroblasts was enhanced, with higher numbers of orthochromatic erythroblasts and enucleated red blood cells (RBCs). pGSN also significantly decreased dysplastic features of cell morphology. Moreover, we found that patients with MDS with multi-lineage dysplasia or with excess blasts-1 showed significantly decreased expression of gelsolin mRNA (GSN) in their peripheral blood. When BM erythroblasts of MDS patients were cultured with pGSN, levels of mRNA transcripts related to terminal erythropoiesis and enucleation were markedly increased, with significantly decreased erythroid dysplasia. Moreover, pGSN treatment enhanced mitochondrial transmembrane potential that is unregulated in MDS and cultured cells. Our findings demonstrate a key role for plasma gelsolin in erythropoiesis and in gelsolin-depleted MDS patients, and raises the possibility that pGSN administration may promote erythropoiesis in erythroid dysplasia.
Highlights
Recent studies have elucidated the complex mechanisms underlying late-stage erythropoiesis by examining the in vitro generation of stem cell-derived red blood cells (RBCs)
When bone marrow (BM) cells derived from patients with myelodysplastic syndrome (MDS) were cultured in the presence of plasma gelsolin (pGSN), the erythroid dysplasia was improved, suggesting its therapeutic potential for MDS patients
The mean percentage of orthochromatic erythroblasts had increased to 27.4% at the high dose of pGSN compared to 18.2% in the controls at 24 h (Figure 3C)
Summary
Recent studies have elucidated the complex mechanisms underlying late-stage erythropoiesis by examining the in vitro generation of stem cell-derived red blood cells (RBCs). There are problems recapitulating this process in vitro, the main issues being delayed maturation, inefficient enucleation, low viability, dysregulated apoptosis, and dysplastic cell features, such as variable cell size and multi-nucleation [1,2,3,4] These effects are thought to be due to the absence of certain stimulatory factors and signals, and to dysregulated autophagy. We hypothesized that the problems associated with in vitro terminal erythropoiesis and dysplastic erythropoiesis, such as poor cell viability, low levels of enucleation, the dysplastic features of nuclei and cytoplasm, and the mitochondrial abnormalities, were partially due to insufficient gelsolin, which is normally supplied to late erythroid cells by macrophages and mesenchymal stem cells. When bone marrow (BM) cells derived from patients with MDS were cultured in the presence of pGSN, the erythroid dysplasia was improved, suggesting its therapeutic potential for MDS patients
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