Lei Ye1, Pengyuan Zhang, Sue Duval, Liping Su, Qiang Xiong, Jianyi Zhang. 1. Division of Cardiology, Department of Medicine (L.Y., P.Z., S.D., L.S., Q.X., J.Z.), Stem Cell Institute (L.Y., J.Z.), and Department of Biomedical Engineering (J.Z.), University of Minnesota, Minneapolis, MN.
Abstract
BACKGROUND: Thymosin β4 (Tβ4) has been shown to enhance the survival of cultured cardiomyocytes. Here, we investigated whether the cytoprotective effects of Tβ4 can increase the effectiveness of transplanted swine mesenchymal stem cells (sMSCs) for cardiac repair in a rat model of myocardial infarction (MI). METHODS AND RESULTS: Under hypoxic conditions, cellular damage (lactate dehydrogenase leakage), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelingc cells), and caspase-8 activity were significantly lower, whereas B-cell lymphoma-extra large protein expression was significantly higher, in sMSCs cultured with Tβ4 (1 μg/mL) than in sMSCs cultured without Tβ4, and Tβ4 also increased sMSC proliferation. For in vivo experiments, animals were treated with basal medium (MI: n=6), a fibrin patch (Patch: n=6), a patch containing sMSCs (sMSC: n=9), or a patch containing sMSCs and Tβ4 (sMSC/Tβ4: n=11); Tβ4 was encapsulated in gelatin microspheres to extend Tβ4 delivery. Four weeks after treatment, echocardiographic assessments of left-ventricular ejection fraction and fractional shortening were significantly better (P<0.05) in sMSC/Tβ4 animals (left-ventricular ejection fraction=51.7 ± 1.1%; fractional shortening=26.7 ± 0.7%) than in animals from MI (39 ± 3%; 19.5 ± 1.7%) and Patch (43 ± 1.4%; 21.6 ± 0.9%) groups. Histological assessment of infarct wall thickness was significantly higher (P<0.05) in sMSC/Tβ4 animals (50%, [45%, 80%]) than in animals from MI (25%, [20%, 25%]) group. Measurements in sMSC (left-ventricular ejection fraction=45 ± 2.6%; fractional shortening=22.9 ± 1.6%; TH = 43% [25%, 45%]), Patch, and MI animals were similar. Tβ4 administration also significantly increased vascular growth, the retention/survival of the transplanted sMSCs, and the recruitment of endogenous c-Kit(+) progenitor cells to the infarcted region. CONCLUSIONS: Extended-release Tβ4 administration improves the retention, survival, and regenerative potency of transplanted sMSCs after myocardial injury.
BACKGROUND: Thymosin β4 (Tβ4) has been shown to enhance the survival of cultured cardiomyocytes. Here, we investigated whether the cytoprotective effects of Tβ4 can increase the effectiveness of transplanted swine mesenchymal stem cells (sMSCs) for cardiac repair in a rat model of myocardial infarction (MI). METHODS AND RESULTS: Under hypoxic conditions, cellular damage (lactate dehydrogenase leakage), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelingc cells), and caspase-8 activity were significantly lower, whereas B-cell lymphoma-extra large protein expression was significantly higher, in sMSCs cultured with Tβ4 (1 μg/mL) than in sMSCs cultured without Tβ4, and Tβ4 also increased sMSC proliferation. For in vivo experiments, animals were treated with basal medium (MI: n=6), a fibrin patch (Patch: n=6), a patch containing sMSCs (sMSC: n=9), or a patch containing sMSCs and Tβ4 (sMSC/Tβ4: n=11); Tβ4 was encapsulated in gelatin microspheres to extend Tβ4 delivery. Four weeks after treatment, echocardiographic assessments of left-ventricular ejection fraction and fractional shortening were significantly better (P<0.05) in sMSC/Tβ4 animals (left-ventricular ejection fraction=51.7 ± 1.1%; fractional shortening=26.7 ± 0.7%) than in animals from MI (39 ± 3%; 19.5 ± 1.7%) and Patch (43 ± 1.4%; 21.6 ± 0.9%) groups. Histological assessment of infarct wall thickness was significantly higher (P<0.05) in sMSC/Tβ4 animals (50%, [45%, 80%]) than in animals from MI (25%, [20%, 25%]) group. Measurements in sMSC (left-ventricular ejection fraction=45 ± 2.6%; fractional shortening=22.9 ± 1.6%; TH = 43% [25%, 45%]), Patch, and MI animals were similar. Tβ4 administration also significantly increased vascular growth, the retention/survival of the transplanted sMSCs, and the recruitment of endogenous c-Kit(+) progenitor cells to the infarcted region. CONCLUSIONS: Extended-release Tβ4 administration improves the retention, survival, and regenerative potency of transplanted sMSCs after myocardial injury.
Authors: Konstantinos E Hatzistergos; Henry Quevedo; Behzad N Oskouei; Qinghua Hu; Gary S Feigenbaum; Irene S Margitich; Ramesh Mazhari; Andrew J Boyle; Juan P Zambrano; Jose E Rodriguez; Raul Dulce; Pradip M Pattany; David Valdes; Concepcion Revilla; Alan W Heldman; Ian McNiece; Joshua M Hare Journal: Circ Res Date: 2010-07-29 Impact factor: 17.367
Authors: Michael Hofmann; Kai C Wollert; Gerd P Meyer; Alix Menke; Lubomir Arseniev; Bernd Hertenstein; Arnold Ganser; Wolfram H Knapp; Helmut Drexler Journal: Circulation Date: 2005-04-25 Impact factor: 29.690
Authors: L H Boise; M González-García; C E Postema; L Ding; T Lindsten; L A Turka; X Mao; G Nuñez; C B Thompson Journal: Cell Date: 1993-08-27 Impact factor: 41.582
Authors: Nicola Smart; Catherine A Risebro; Athalie A D Melville; Kelvin Moses; Robert J Schwartz; Kenneth R Chien; Paul R Riley Journal: Nature Date: 2006-11-15 Impact factor: 49.962
Authors: Jeffrey E Cohen; Brendan P Purcell; John W MacArthur; Anbin Mu; Yasuhiro Shudo; Jay B Patel; Christopher M Brusalis; Alen Trubelja; Alexander S Fairman; Bryan B Edwards; Mollie S Davis; George Hung; William Hiesinger; Pavan Atluri; Kenneth B Margulies; Jason A Burdick; Y Joseph Woo Journal: Circ Heart Fail Date: 2014-06-05 Impact factor: 8.790
Authors: Sebastian Schafer; Sivakumar Viswanathan; Anissa A Widjaja; Wei-Wen Lim; Aida Moreno-Moral; Daniel M DeLaughter; Benjamin Ng; Giannino Patone; Kingsley Chow; Ester Khin; Jessie Tan; Sonia P Chothani; Lei Ye; Owen J L Rackham; Nicole S J Ko; Norliza E Sahib; Chee Jian Pua; Nicole T G Zhen; Chen Xie; Mao Wang; Henrike Maatz; Shiqi Lim; Kathrin Saar; Susanne Blachut; Enrico Petretto; Sabine Schmidt; Tracy Putoczki; Nuno Guimarães-Camboa; Hiroko Wakimoto; Sebastiaan van Heesch; Kristmundur Sigmundsson; See L Lim; Jia L Soon; Victor T T Chao; Yeow L Chua; Teing E Tan; Sylvia M Evans; Yee J Loh; Muhammad H Jamal; Kim K Ong; Kim C Chua; Boon-Hean Ong; Mathew J Chakaramakkil; Jonathan G Seidman; Christine E Seidman; Norbert Hubner; Kenny Y K Sin; Stuart A Cook Journal: Nature Date: 2017-11-13 Impact factor: 49.962