Abstract
NFAT (Nuclear Factor of Activated T cells) is a family of five calcium-induced, calcineurin-dependent transcription factors, characterized as master regulators of inducible gene expression in T lymphocytes. In various tissues (including bone, cartilage and adipose tissue), NFAT factors have also been found to regulate processes of cellular adaptation and differentiation. NFAT family members are also expressed in human CD34+ hematopoietic progenitor cells as well as in mesenchymal stem cells; however, a biological function of NFAT in these cells, such as a role in hematopoietic differentiation, has not yet been described. To determine a potential role for NFAT in hematopoiesis, we characterized the steady-state hematopoiesis in NFATc2 knockout (KO) mice by analyzing peripheral blood, bone marrow and extramedullary tissue (spleen and liver) of KO and age-matched wildtype (WT) mice by cytology, histopathology as well as flow cytometry. No significant abnormalities were observed in KO mice of young age (6–12 weeks). NFATc2 KO mice of older age (>12 months), however, were found to be anemic, with a significant decrease in red blood cell counts as well as in hemoglobin and hematocrit values, and also showed decreased numbers of peripheral blood platelets as compared to the WT. In contrast, no significant differences between WT and KO were found in total counts of white blood cells or in leukocyte differentials. Femora of NFATc2 KO mice appeared macroscopically pale and, upon elutriation, gave yield to less than 50% of bone marrow cells compared to the WT, indicating bone marrow hypoplasia. Further analysis of bone marrow differentials by morphology and flow cytometry showed a profound decrease in erythroid cells as well as in megakaryocytes. Histopathological examination of KO bone marrow sections revealed evidence of bone marrow sclerosis, as indicated by an increase in bone trabeculae and osteoblasts within the marrow space. In some mice, an increase in reticulin fiber content was also noted. Interestingly, both liver and spleens of NFATc2 KO mice showed clear evidence for extramedullary hematopoiesis, suggesting that displacement of hematopoietic cells by the bone marrow stroma may be a possible cause of the observed cytopenias.
These results show that NFATc2 knockout mice over their lifespan develop a phenotype, which clinically resembles human osteomyelofibrosis/-sclerosis. The underlying mechanism for the observed hematopoietic abnormalities has to be defined, in particular the respective contribution of hematopoietic and bone marrow stroma cells. Given that NFAT factors are expressed at considerable levels in both hematopoietic progenitor cells and mesenchymal stem cells, our results should encourage further studies on the yet undefined role of these transcription factors within the bone marrow hematopoietic niche.
Fine-Tuning Reception in the Bone: PPARγand Company
