ABSTRACT
Bone marrow mesenchymal stromal cells (MSCs) have been implicated in the microenvironmental support of hematopoietic stem cells (HSCs) and often co-transplanted with HSCs to facilitate recovery of ablated bone marrows. However, the precise effect of transplanted MSCs on HSC regeneration remains unclear because the kinetics of HSC self-renewal in vivo after co-transplantation has not been monitored. In this study, we examined the effects of intrafemoral injection of MSCs on HSC self-renewal in rigorous competitive repopulating unit (CRU) assays using congenic transplantation models in which stromal progenitors (CFU-F) were ablated by irradiation. Interestingly, naive MSCs injected into femur contributed to the reconstitution of a stromal niche in the ablated bone marrows, but did not exert a stimulatory effect on the in-vivo self-renewal of co-transplanted HSCs regardless of the transplantation methods. In contrast, HSC self-renewal was four-fold higher in bone marrows intrafemorally injected with beta-catenin-activated MSCs. These results reveal that naive MSCs lack a stimulatory effect on HSC self-renewal in-vivo and that stroma must be activated during recoveries of bone marrows. Stromal targeting of wnt/beta-catenin signals may be a strategy to activate such a stem cell niche for efficient regeneration of bone marrow HSCs.
Subject(s)
Animals , Mice , Bone Marrow/metabolism , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/pathology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Mice, Inbred C57BL , Radiation Chimera , Regeneration , Stem Cell Niche/metabolism , Stromal Cells/metabolism , Transplantation Conditioning , beta Catenin/metabolismSubject(s)
Animals , History, 19th Century , History, 20th Century , Humans , Mice , Hematopoietic Stem Cell Transplantation/history , Academies and Institutes , Anemia, Aplastic/surgery , Bone Marrow Transplantation/history , Cord Blood Stem Cell Transplantation/history , Hospitals, Public , Hematologic Neoplasms/surgery , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/trends , Mexico , Models, Animal , Radiation Chimera , Transplantation, Homologous , United StatesABSTRACT
Haemopoiesis in mammals takes place in yolk-sac and in mouse it can be detected on the 7th day of gestation. Erythropoietin (EPO) responsive cells can be detected from 7th day onwards. However, the cells committed to the myeloid lineage which can respond to the haemopoietic growth factor (viz. granulocyte macrophage colony stimulating factor; GM-CSF) can be demonstrated only on 10th day of gestation. At the same time, the 12-day spleen colony forming cells i.e. the late colony forming unit spleen (CFU-s) which are multipotent stem cells can also be detected. Data suggest that the stem cells seen in the embryo from 7-10 days of gestation may be a primitive population confined only to the yolk-sac. Liver haemopoiesis which begins in the liver of 13-day embryos is due to primitive haemopoietic pluripotent stem cells, arising de novo in the embryo and not in the yolk-sac, since no primitive pluripotent stem cells capable of repopulating lethally irradiated bone-marrow can be detected in the yolk-sac.