Die Rolle intrinsischer und extrinsischer Faktoren in der Vermittlung einer altersbedingten Beeinträchtigung der Knochenstammzellfunktion
Zusammenfassung der Projektergebnisse
Skeletal aging and disease are associated with a disruption of the delicate balance between the opposing actions of osteoblasts and osteoclasts that are responsible for maintaining the integrity of bone tissues. My results could show, through detailed functional as well as single-cell genomic studies, that intrinsic aging of mouse skeletal stem cells (mSSCs) alters niche signaling and skews lineage output thereby generating an aged bone marrow niche characterized by increased osteoclastogenesis and simultaneous attrition of osteochondrogenic capacity. I have identified Csf1-Csf1r (Colony stimulating factor-1 – Colony stimulating factor-1 receptor) signaling as the main mediator of skeletal and hematopoietic lineage interaction upregulated during aging. Strikingly, age-related aberrations originate intrinsically from the mSSC lineage as evidenced by the observation that exposure to a youthful circulation by heterochronic parabiosis or reconstitution with young hematopoietic stem cells failed to improve bone parameters in aged mice. High levels of recombinant Csf1 impaired fracture healing in young mice while genetic ablation of Csf1 reduced bone loss with age. Bone regeneration experiments further showed that local application of a finely tuned dose of a small molecule blocker for Csf1 in combination with Bmp2 is necessary for successful rejuvenation through the skeletal stem cell pool. My findings provide mechanistic insight into the complex, multifactorial mechanisms underlying stem cell aging and offer new prospects for rejuvenating the aged skeletal system by targeting the bone marrow niche.
Projektbezogene Publikationen (Auswahl)
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Identification of the Human Skeletal Stem Cell. Cell 2018; 175(1): 43–56.e21
Charles K. F. Chan, Gunsagar S. Gulati, Rahul Sinha, Justin Vincent Tompkins, Michael Lopez, Ava C. Carter, Ryan C. Ransom, Andreas Reinisch, Taylor Wearda, Matthew Murphy, Rachel E. Brewer, Lauren S. Koepke, Owen Marecic, Anoop Manjunath, Eun Young Seo, Tripp Leavitt, Wan-Jin Lu, Allison Nguyen, Stephanie D. Conley, Ankit Salhotra, Thomas H. Ambrosi, Mimi R. Borrelli, Taylor Siebel, Karen Chan, Katharina Schallmoser, Jun Seita, Debashis Sahoo, Henry Goodnough, Julius Bishop, Michael Gardner, Ravindra Majeti, Derrick C. Wan, Stuart Goodman, Irving L. Weissman, Howard Y. Chang, and Michael T. Longaker
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A Revised Perspective of Skeletal Stem Cell Biology. Front Cell Dev Biol. 2019; 7:189
Thomas H. Ambrosi, Michael T. Longaker, Charles K. F. Chan
