Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration

• Published in: Blood Vol. 119; no. 23; pp. 5429 - 5437
• Main Authors: Nakamura-Ishizu, Ayako, Okuno, Yuji, Omatsu, Yoshiki, Okabe, Keisuke, Morimoto, Junko, Uede, Toshimitsu, Nagasawa, Takashi, Suda, Toshio, Kubota, Yoshiaki
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 07.06.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Animals; Biological and medical sciences; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - radiation effects; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; Cell Proliferation; Endothelial Cells - cytology; Endothelial Cells - metabolism; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Gene Deletion; Hematologic and hematopoietic diseases; Hematopoiesis; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Integrin alpha Chains - genetics; Medical sciences; Mice; Mice, Inbred C57BL; RNA, Messenger - genetics; Stromal Cells - cytology; Stromal Cells - metabolism; Tenascin - analysis; Tenascin - genetics; Tenascin - metabolism; Up-Regulation; Whole-Body Irradiation; Regeneration; Hematology; Tenascin C; Cell microenvironment; Extracellular matrix; Protein C; Natural anticoagulant
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-11-393645

The BM microenvironment is required for the maintenance, proliferation, and mobilization of hematopoietic stem and progenitor cells (HSPCs), both during steady-state 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 steady-state hematopoiesis; however, they failed to reconstitute hematopoiesis after BM ablation and showed high lethality. The capacity to support transplanted wild-type 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 α9–dependent manner and up-regulated the expression of the cyclins (cyclinD1 and cyclinE1) and down-regulated the expression of the cyclin-dependent kinase inhibitors (p57Kip2, p21Cip1, p16Ink4a). These results identify TN-C as a critical component of the BM microenvironment that is required for hematopoietic regeneration.