Abstract
Bone marrow stromal stem cells (BMSSCs) are mesenchymal stem cells that are capable of differentiating into osteoblasts, chondrocytes, adipocytes, muscle cells and neural cells. Upon in vivo transplantation, BMSSCs form bone and associated hematopoietic marrow elements. However, the functional role of BMSSC-associated bone marrow is still unknown. In this study, we demonstrated that human BMSSCs organized ectopic bone marrow niche microarchitecture that contained hematopoietic progenitors and multiple lineages of cells including myeloid, lymphoid, erythroid and megakaryocytic cells originated from recipients. Significantly, transplantation of the ectopically generated bone marrow cells can rescue lethally irradiated mice with successful hematopoietic engraftment, suggesting a therapeutic potentiality of human BMSSC-organized hematopoietic progenitor cells. In addition, systemically administrated bone marrow cells derived from long bones of donor mice homed to BMSSC-associated ectopic bone marrow niche microenvironments. These data demonstrate that BMSSC-organized ectopic bone marrow has functional analogy to physiological bone marrow. Mechanistically, platelet-derived growth factor (PDGF)-BB was found to promote hematopoiesis in the BMSSC transplants through an up-regulated expression of β-catenin. Conversely, inhibition of PDGF signaling in BMSSCs by PDGF receptor β siRNA blocked hematopoiesis and osteogenesis in the BMSSC transplants. Moreover, the BMSSC-organized ectopic bone/marrow structure could be utilized as an organ to be re-transplanted into secondary recipient mice to deliver hematopoietic cells in the recipient’s circulation system, implying a therapeutic potential of transplanting bone/marrow organ system containing hematopoietic stem cell niches. In summary, these evidences demonstrate that regeneration of BMSSC-organized functional bone marrow niches contain hematopoietic progenitor/stem cells and therefore provide promise for clinical therapy.
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