Abstract
Bone marrow mesenchymal stem and progenitor cells (BM-MSPCs) maintain homeostasis of bone tissue by providing osteoblasts. Although several markers have been identified for labeling of MSPCs, these labeled cells still contain non-BM-MSPC populations. Studies have suggested that MSPCs are observed as leptin receptor (LepR)-positive cells, whereas osteoblasts can be classified as positive for Runx2, a master regulator for osteoblastogenesis. Here, we demonstrate, using Runx2-GFP reporter mice, that the LepR-labeled population contains Runx2-GFPlow sub-population, which possesses higher fibroblastic colony-forming units (CFUs) and mesensphere capacity, criteria for assessing stem cell activity, than the Runx2-GFP− population. In response to parathyroid hormone (PTH), a bone anabolic hormone, LepR+Runx2-GFPlow cells increase Runx2 expression and form multilayered structures near the bone surface. Subsequently, the multilayered cells express Osterix and Type I collagen α, resulting in generation of mature osteoblasts. Therefore, our results indicate that Runx2 is weakly expressed in the LepR+ population without osteoblastic commitment, and the LepR+Runx2-GFPlow stromal cells sit atop the BM stromal hierarchy.
Highlights
Potential to form CFU-F colonies or clonal mesenspheres[6, 7, 11]
The expression levels of all three of these MSPC markers in the LepR-Cre/Tomato+Runx2-GFPlow sub-population were significantly higher than in the LepR-Cre/Tomato+Runx2-GFP− sub-population (Fig. 3L–N). These results indicated that the LepR-Cre/Tomato+Runx2-GFPlow sub-population overlaps with CXCL12 abundant reticular (CAR) cells[23], which are generated from part of the developing chondrogenic cell populations[17]
We report that BM-MSPCs in adult BM are confined to the weak Runx2-GFP-expressing LepR+ stromal cell population, which differentiates into Col1+ mature osteoblasts in response to parathyroid hormone (PTH) anabolic effects
Summary
Mengyu Yang[1], Atsushi Arai[2], Nobuyuki Udagawa[3], Toru Hiraga[4], Zhao Lijuan[1], Susumu Ito[5], Toshihisa Komori[6], Takeshi Moriishi[6], Koichi Matsuo[7], Kouji Shimoda[8], Ali H. These results suggest that the anabolic effects of PTH on bone tissue are exerted by the acceleration of osteoblastogenesis from immature BM mesenchymal precursors It still remains unclear which BM stromal cells give rise to osteoblasts in response to PTH treatments, thereby mediating the therapeutic response in osteoporosis. Our studies have shown that the LepR+Runx2-GFPlow cells differentiate into mature osteoblasts via multilayered cell formation adjacent to bone surfaces in response to PTH-induced bone anabolic effects. These results provide evidence that LepR+Runx2-GFPlow cells sit atop the BM mesenchymal stromal cell hierarchy
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