Rejuvenation of aged hematopoietic stem cells and endothelial niches by thrombospondin-1 blockade

通过血小板反应蛋白-1 阻断使衰老的造血干细胞和内皮微环境恢复活力

• 批准号: 10634625
• 负责人: Jason Mathew Butler
• 金额: $ 49.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634625
• 关键词: Activities of Daily Living; Address; Adult; Affect; Aging; Animal Model; Animals; Antibodies; Back; Blood; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cell Therapy; Cells; Clinical Trials; Coculture Techniques; Defect; Development; Disease; Elderly; Endothelial Cells; Endothelium; Engraftment; Equilibrium; Exhibits; FRAP1 gene; Failure; Foundations; Genetic Transcription; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; In Vitro; Individual; Infusion procedures; Injury; Knock-out; Laboratories; Life; Longevity; Maintenance; Measures; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myelosuppression; Natural regeneration; Organ; Output; Pathway interactions; Phenotype; Physiological; Predisposition; Premature aging syndrome; Process; Proteomics; Proto-Oncogene Proteins c-akt; Recovery; Rejuvenation; Reporter; Research Proposals; Risk; Screening procedure; Signal Transduction; System; Testing; Therapeutic; Thrombospondin 1; Time; Tissues; Vascular System; age related; aged; anti aging; arteriole; body system; bone; bone aging; cell type; cytopenia; design; experimental study; functional restoration; healthspan; hematopoietic stem cell aging; hematopoietic stem cell expansion; hematopoietic stem cell self-renewal; improved; in vitro Model; in vivo; inhibiting antibody; insight; mortality; mouse model; neutralizing antibody; new therapeutic target; novel; paracrine; preclinical trial; premature; preservation; repaired; self-renewal; stem cell function; success; synergism; tool; transcriptomics

PROJECT SUMMARY There is a substantial need for the development of preventative and therapeutic options to delay the aging process, to rejuvenate tissue/organs, and to enhance regeneration and repair. Aging of the blood system is associated with loss of vascular integrity and dramatic changes in hematopoietic stem cell (HSC) function. In addition to increasing in number and losing self-renewal potential, old HSCs exhibit a myeloid bias and increased propensity to develop hematologic malignancies. While some of these changes reflect cell-intrinsic alterations, emerging evidence suggests that some of these defects may also be regulated by the bone marrow (BM) microenvironment, in particular the BM endothelial niche. In particular, we have demonstrated that the BM endothelial niche is indispensable for supporting the balance between HSC self-renewal and differentiation following myeloablative insult. We have also shown that AKT/mTOR signaling in BM endothelial cells (BMECs) is required for maintenance of the HSCs and that this signaling is disrupted in aged BMECs. To ask how a disruption of the AKT/mTOR signaling axis in ECs affects the hematopoietic system, we have conditionally deleted mTOR in adult ECs (mTOR(ECKO) mice) and found that this deletion resulted in the premature aging of HSCs as demonstrated by their phenotypic, functional, and transcriptional analysis. To better understand how EC-mediated signaling drives the aging of the hematopoietic system, we utilized our mTOR(ECKO) mouse model as a screening tool to discover as yet unknown pro-HSC-aging factors. Transcriptomic and proteomic studies identified Thrombospondin-1 (TSP1) as a candidate pro-aging factor that was commonly upregulated in mTOR(ECKO) and aged mice when compared to young controls. Moreover, global knockout of TSP1 resulted in preservation and rejuvenation of HSC function in aged mice. This research proposal is designed to test whether it is possible to: 1) reverse the age-related phenotypes of the hematopoietic and vascular systems by global or cell-specific deletion, or antibody-mediated inhibition, of TSP1, 2) enhance the ex vivo expansion and function of aged HSC by exogenous inhibition of TSP1, and 3) rejuvenate an aged BM microenvironment following myelosuppressive treatments by utilizing young BMECs as a cellular therapeutic with or without the co-infusion of a neutralizing antibody to TSP1. The proposed studies will utilize novel in vivo and in vitro models developed in our lab and, if successful, will unlock the therapeutic potential of TSP1 inhibition to improve overall healthspan, longevity, and regeneration of the hematopoietic system in the elderly. The success of this research proposal will open up new avenues for the development of a wide array of therapeutic strategies designed as an effective means to reverse age-related hematopoietic deficiencies.

项目总结

项目成果

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response.

• DOI: 10.1038/s41467-023-37783-4
• 发表时间: 2023-04-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ramalingam, Pradeep;Gutkin, Michael C.;Poulos, Michael G.;Tillery, Taylor;Doughty, Chelsea;Winiarski, Agatha;Freire, Ana G.;Rafii, Shahin;Redmond, David;Butler, Jason M.
• 通讯作者: Butler, Jason M.