BACKGROUND: Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro-fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. METHODS: We used a TSP-2 knockout (KO) mouse in conjunction with a fetal murine cardiomyocyte grafting model to evaluate the effects of a lack of TSP-2 on fibrosis, vascular density, and graft size in the heart. RESULTS: Two weeks after grafting in the uninjured heart, fibrosis area was reduced 4.5-fold in TSP-2 KO mice, and the thickness of the peri-graft scar capsule was reduced sevenfold compared to wild-type (WT). Endothelial cell density in the peri-graft region increased 2.5-fold in the absence of TSP-2, and cardiomyocyte graft size increased by 46% in TSP-2 KO hearts. CONCLUSIONS: TSP-2 is a key regulator of fibrosis and angiogenesis following cell grafting in the heart, and its absence promotes better graft integration, vascularization, and survival. SUMMARY: Fibrosis around cardiac cell injections impairs graft integration in cell-based cardiac repair. TSP-2 is a pro-fibrotic, anti-angiogenic matricellular protein. Using a TSP-2-knockout mouse model and cardiac cell transplantation, we found significantly reduced fibrosis and increased endothelial cell density in the peri-graft region. Thus, TSP-2 is an attractive target for therapeutic knockdown to improve cardiac graft integration and survival.
BACKGROUND:Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro-fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. METHODS: We used a TSP-2 knockout (KO) mouse in conjunction with a fetal murine cardiomyocyte grafting model to evaluate the effects of a lack of TSP-2 on fibrosis, vascular density, and graft size in the heart. RESULTS: Two weeks after grafting in the uninjured heart, fibrosis area was reduced 4.5-fold in TSP-2 KO mice, and the thickness of the peri-graft scar capsule was reduced sevenfold compared to wild-type (WT). Endothelial cell density in the peri-graft region increased 2.5-fold in the absence of TSP-2, and cardiomyocyte graft size increased by 46% in TSP-2 KO hearts. CONCLUSIONS:TSP-2 is a key regulator of fibrosis and angiogenesis following cell grafting in the heart, and its absence promotes better graft integration, vascularization, and survival. SUMMARY:Fibrosis around cardiac cell injections impairs graft integration in cell-based cardiac repair. TSP-2 is a pro-fibrotic, anti-angiogenic matricellular protein. Using a TSP-2-knockout mouse model and cardiac cell transplantation, we found significantly reduced fibrosis and increased endothelial cell density in the peri-graft region. Thus, TSP-2 is an attractive target for therapeutic knockdown to improve cardiac graft integration and survival.
Authors: Gregory L Brower; Jason D Gardner; Mary F Forman; David B Murray; Tetyana Voloshenyuk; Scott P Levick; Joseph S Janicki Journal: Eur J Cardiothorac Surg Date: 2006-08-28 Impact factor: 4.191
Authors: Blanche Schroen; Stephane Heymans; Umesh Sharma; W Matthijs Blankesteijn; Saraswati Pokharel; Jack P M Cleutjens; J Gordon Porter; Chris T A Evelo; Rudy Duisters; Rick E W van Leeuwen; Ben J A Janssen; Jacques J M Debets; Jos F M Smits; Mat J A P Daemen; Harry J G M Crijns; Paul Bornstein; Yigal M Pinto Journal: Circ Res Date: 2004-07-29 Impact factor: 17.367
Authors: T R Kyriakides; Y H Zhu; L T Smith; S D Bain; Z Yang; M T Lin; K G Danielson; R V Iozzo; M LaMarca; C E McKinney; E I Ginns; P Bornstein Journal: J Cell Biol Date: 1998-01-26 Impact factor: 10.539
Authors: David M Charytan; Robert Padera; Alexander M Helfand; Michael Zeisberg; Xingbo Xu; Xiaopeng Liu; Jonathan Himmelfarb; Angeles Cinelli; Raghu Kalluri; Elisabeth M Zeisberg Journal: Int J Cardiol Date: 2014-07-06 Impact factor: 4.164
Authors: Robert M Jackson; Beth A Griesel; Kevin R Short; David Sparling; Willard M Freeman; Ann Louise Olson Journal: Obesity (Silver Spring) Date: 2019-12 Impact factor: 5.002
Authors: Dimitry A Chistiakov; Alexandra A Melnichenko; Veronika A Myasoedova; Andrey V Grechko; Alexander N Orekhov Journal: Int J Mol Sci Date: 2017-07-17 Impact factor: 5.923
Authors: Ellen A Tsai; Melissa A Gilbert; Christopher M Grochowski; Lara A Underkoffler; He Meng; Xiaojie Zhang; Michael M Wang; Hailu Shitaye; Kurt D Hankenson; David Piccoli; Henry Lin; Binita M Kamath; Marcella Devoto; Nancy B Spinner; Kathleen M Loomes Journal: Cell Mol Gastroenterol Hepatol Date: 2016-05-26