Skeletal development and the hematopoietic niche

骨骼发育和造血生态位

• 批准号: 8713978
• 负责人: Olena Jacenko
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713978
• 关键词: Adolescent; Adult; Affect; Aging; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Bone Surface; Cartilage; Cartilage Matrix; Cell Differentiation process; Cell Transplantation; Cell physiology; Cells; Chondrocytes; Collagen; Data; Defect; Development; Diagnosis; Disease; Environment; Genetically Engineered Mouse; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homing; Immune; Immune System Diseases; Immune system; Impairment; Incidence; Knockout Mice; Label; Laboratories; Lymphocyte; Lymphopoiesis; Maintenance; Malignant Neoplasms; Marrow; Mediating; Microscopy; Mus; Neonatal; Osteoblasts; Pancytopenia; Phenotype; Principal Investigator; Process; Proteins; Regulation; Skeletal Development; Skeletal system; Skeleton; Stem cells; System; Tamoxifen; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Transplantation; base; bone; cartilage matrix protein; disease phenotype; field study; immune function; in vivo; in vivo imaging; innovation; insight; intravital imaging; osteoprogenitor cell; progenitor; programs; promoter; public health relevance; reconstitution; skeletal; skeletal tissue; skeletogenesis; stem; stem cell biology; stem cell niche; substantia spongiosa; two-photon

DESCRIPTION (provided by applicant): Certain immuno-osseous and hematopoietic disorders likely result from an impaired hematopoietic niche, which in turn may ensue from defective endochondral ossification (EO), where a cartilage skeletal blueprint is replaced by trabecular bone and marrow. This proposal will test our hypothesis that the EO- derived chondro-osseous junction (COJ), comprised of hypertrophic cartilage and trabecular bone, is a key hematopoietic niche within the marrow. This hypothesis stems from our transgenic (Tg) and null mice for collagen X, a matrix protein expressed in hypertrophic cartilage prior to EO. Mice with disrupted collagen X function display skeleto-hematopoietic defects including altered hypertrophic cartilage and trabecular bone in the COJ, marrow hypoplasia, diminished lymphopoiesis, and impaired immune function. We propose that these defects stem from an altered hematopoietic niche within the COJ, and that these mice provide an innovative system to identify the mechanistic basis for niche-mediated disorders. The goals of this proposal are to implicate a subset of COJ progenitors and collagen X as key regulators of the hematopoietic niche by: 1) Assessing by bone marrow transplantation if all hematopoietic defects in the collagen X mice could be attributed to niche impairment and whether homing of transplanted HSCs to the COJ niche could be visualized via two-photon microscopy; 2) Testing the ability of EO-progenitors from control and collagen X mice to reconstitute an ectopic COJ and HSC niche upon transplantation; and 3) Determining if EO-derived osteoprogenitors require collagen X for niche establishment and/or niche maintenance.

描述(申请人提供)：某些免疫性骨性和造血性疾病可能是由于造血骨龛受损，继而可能是软骨内骨化(EO)缺陷所致，软骨骨骼蓝图被小梁骨和骨髓取代。这一建议将检验我们的假设，即EO来源的软骨-骨连接(CoJ)由肥大的软骨和松质骨组成，是骨髓中关键的造血生态位。这一假说源于我们的转基因(TG)小鼠和空白小鼠的X胶原蛋白，这是一种在EO之前在肥大软骨中表达的基质蛋白。X型胶原功能受损的小鼠表现为骨骼造血缺陷，包括CoJ肥大的软骨和小梁骨改变，骨髓发育不良，淋巴细胞生成减少，免疫功能受损。我们认为这些缺陷源于CoJ内的造血生态位的改变，这些小鼠提供了一个创新的系统来识别生态位介导的疾病的机制基础。该建议的目的是通过以下方式暗示COJ前体细胞和X胶原蛋白作为造血生态位的关键调节因子：1)通过骨髓移植评估X胶原蛋白小鼠的所有造血缺陷是否都可归因于骨龛受损，以及移植后的HSCs是否可以通过双光子显微镜观察到COJ壁龛的归巢；2)测试对照组和X胶原小鼠的EO祖细胞在移植后重建异位CoJ和HSC壁龛的能力；以及3)确定EO来源的骨祖细胞是否需要X胶原蛋白来建立和/或维持壁龛。