The BM microenvironment is required for the maintenance, proliferation, and mobilization of hematopoietic stem and progenitor cells (HSPCs), both during steadystate conditions and hematopoietic recovery after myeloablation. The ECM meshwork has long been recognized as a major anatomical component of the BM microenvironment; however, the molecular signatures and functions of the ECM to support HSPCs are poorly understood. Of the many ECM proteins, the expression of tenascin-C (TN-C) was found to be dramatically up-regulated during hematopoietic recovery after myeloablation. The TN-C gene was predominantly expressed in stromal cells and endothelial cells, known as BM niche cells, supporting the function of HSPCs. Mice lacking TN-C (TN-C ؊/؊ ) mice showed normal steadystate hematopoiesis; however, they failed to reconstitute hematopoiesis after BM ablation and showed high lethality. The capacity to support transplanted wildtype hematopoietic cells to regenerate hematopoiesis was reduced in TN-C ؊/؊ recipient mice. In vitro culture on a TN-C substratum promoted the proliferation of HSPCs in an integrin ␣9-dependent manner and up-regulated the expression of the cyclins (cyclinD1 and cyclinE1) and down-regulated the expression of the cyclin-dependent kinase inhibitors (p57 Kip2 IntroductionThe BM is the main hematopoietic organ in the adult. It provides an efficient microenvironment for hematopoiesis, which contributes to the maintenance, proliferation, and differentiation of hematopoietic stem and progenitor cells (HSPCs). A wellaccepted concept regarding the hematopoietic microenvironment is that of the hematopoietic stem cell (HSC) niche. 1-3 The HSC niche is subdivided into the osteoblastic niche 4-7 and the vascular niche. 8,9 The BM vasculature is surrounded by perivascular niche cells such as macrophages 10,11 and stromal cells (ie, reticular cells) of mesenchymal lineage, 12,13 which cooperatively regulate HSC activity.In contrast to the well-investigated cellular niches, the functions of ECM proteins as a niche are poorly understood. The ECM of the BM comprises fibrous proteins such as types I and IV collagen and fibronectin (FN) 14 and nonfibrous proteins such as tenascin-C (TN-C). 15 We have shown previously that longterm bromodeoxyuridine (BrdU)-label-retaining cells reside in the hypoxic areas distant from the endothelial tubes closely attached to nonendothelial ECM structures. 16 In vitro culture systems also suggest the importance of the ECM in the maintenance of HSPCs. 17 Therefore, a role for the ECM as a BM niche has been suggested, yet little is known about how the ECM affects HSPCs in vivo.TN-C is a highly conserved ECM glycoprotein that is expressed mainly during embryogenesis. 18 TN-C-deficient mice show normal development with no defects in gross organization. 18 In adult tissues, TN-C expression is restricted to sites of active tissue remodeling (eg, inflammation 19,20 and wound healing 21 ) and plays a significant function in these pathologies. [19][20][21] Expression of TN-C in the BM is l...

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Bone marrow-derived cells (BMDCs) contribute to postnatal vascular growth by differentiating into endothelial cells or secreting angiogenic factors. However, the extent of their endothelial differentiation highly varies according to the angiogenic models used. Wound healing is an intricate process in which the skin repairs itself after injury. As a process also observed in cancer progression, neoangiogenesis into wound tissues is profoundly involved in this healing process, suggesting the contribution of BMDCs. However, the extent of the differentiation of BMDCs to endothelial cells in wound healing is unclear. In this study, using the green fluorescent protein-bone marrow chimeric experiment and high resolution confocal microscopy at a single cell level, we observed no endothelial differentiation of BMDCs in 2 acute wound healing models (dorsal excisional wound and ear punch) and a chronic wound healing model (decubitus ulcer). Instead, a major proportion of BMDCs were macrophages. Indeed, colony-stimulating factor 1 (CSF-1) inhibition depleted approximately 80% of the BMDCs at the wound healing site. CSF-1-mutant (CSF-1 op/op ) mice showed significantly reduced neoangiogenesis into the wound site, supporting the substantial role of BMDCs as macrophages. Our data show that the proangiogenic effects of macrophages, but not the endothelial differentiation, are the major contribution of