BACKGROUND AIMS: We have shown previously that inhibition of the p38 mitogen-activated protein kinase (p38MAPK) directs the differentiation of human embryonic stem cell (hESC)-derived cardiomyocytes (hCM). We investigated the therapeutic benefits of intramyocardial injection of hCM differentiated from hESC by p38MAPK inhibition using closed-chest ultrasound-guided injection at a clinically relevant time post-myocardial infarction (MI) in a mouse model. METHODS: MI was induced in mice and the animals treated at day 3 with: (a) hCM, (b) human fetal fibroblasts (hFF) as cell control, or (c) medium control (n = 10 animals/group). Left ventricular ejection fraction (LVEF) was evaluated post-MI prior to therapy, and at days 28 and 60 post-cell therapy. Hearts were analyzed at day 60 for infarct size, angiogenesis, cell fate and teratoma formation. RESULTS: LVEF was improved in the hCM-treated animals compared with both hFF and medium control-treated animals at day 28 (39.03 ± 1.79% versus 27.89 ± 1.27%, P < 0.05, versus 32.90 ± 1.46%, P < 0.05, respectively), with sustained benefit until day 60. hCM therapy resulted in significantly smaller scar size, increased capillary bed area, increased number of arterioles, less native cardiomyocyte (CM) apoptosis, and increased CM proliferation compared with the other two groups. These benefits were achieved despite a very low retention rate of the injected cells at day 60, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Therapy with hCM did not result in intramyocardial teratoma formation at day 60. CONCLUSIONS: This study demonstrates that hCM derived from p38MAPK-treated hESC have encouraging therapeutic potential.
BACKGROUND AIMS: We have shown previously that inhibition of the p38 mitogen-activated protein kinase (p38MAPK) directs the differentiation of human embryonic stem cell (hESC)-derived cardiomyocytes (hCM). We investigated the therapeutic benefits of intramyocardial injection of hCM differentiated from hESC by p38MAPK inhibition using closed-chest ultrasound-guided injection at a clinically relevant time post-myocardial infarction (MI) in a mouse model. METHODS:MI was induced in mice and the animals treated at day 3 with: (a) hCM, (b) human fetal fibroblasts (hFF) as cell control, or (c) medium control (n = 10 animals/group). Left ventricular ejection fraction (LVEF) was evaluated post-MI prior to therapy, and at days 28 and 60 post-cell therapy. Hearts were analyzed at day 60 for infarct size, angiogenesis, cell fate and teratoma formation. RESULTS: LVEF was improved in the hCM-treated animals compared with both hFF and medium control-treated animals at day 28 (39.03 ± 1.79% versus 27.89 ± 1.27%, P < 0.05, versus 32.90 ± 1.46%, P < 0.05, respectively), with sustained benefit until day 60. hCM therapy resulted in significantly smaller scar size, increased capillary bed area, increased number of arterioles, less native cardiomyocyte (CM) apoptosis, and increased CM proliferation compared with the other two groups. These benefits were achieved despite a very low retention rate of the injected cells at day 60, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Therapy with hCM did not result in intramyocardial teratoma formation at day 60. CONCLUSIONS: This study demonstrates that hCM derived from p38MAPK-treated hESC have encouraging therapeutic potential.
Authors: Matthew L Springer; Richard E Sievers; Mohan N Viswanathan; Michael S Yee; Elyse Foster; William Grossman; Yerem Yeghiazarians Journal: Am J Physiol Heart Circ Physiol Date: 2005-05-20 Impact factor: 4.733
Authors: Theo Kofidis; Darren R Lebl; Rutger-Jan Swijnenburg; Joan M Greeve; Uwe Klima; Joseph Gold; Chunhui Xu; Robert C Robbins Journal: Eur J Cardiothorac Surg Date: 2005-12-06 Impact factor: 4.191
Authors: D Orlic; J Kajstura; S Chimenti; F Limana; I Jakoniuk; F Quaini; B Nadal-Ginard; D M Bodine; A Leri; P Anversa Journal: Proc Natl Acad Sci U S A Date: 2001-08-14 Impact factor: 11.205
Authors: Leora B Balsam; Amy J Wagers; Julie L Christensen; Theo Kofidis; Irving L Weissman; Robert C Robbins Journal: Nature Date: 2004-03-21 Impact factor: 49.962
Authors: Jianqin Ye; Andrew Boyle; Henry Shih; Richard E Sievers; Yan Zhang; Megha Prasad; Hua Su; Yan Zhou; William Grossman; Harold S Bernstein; Yerem Yeghiazarians Journal: PLoS One Date: 2012-01-17 Impact factor: 3.240
Authors: Kurosh Ameri; Arman Jahangiri; Anthony M Rajah; Kathryn V Tormos; Ravi Nagarajan; Melike Pekmezci; Vien Nguyen; Matthew L Wheeler; Michael P Murphy; Timothy A Sanders; Stefanie S Jeffrey; Yerem Yeghiazarians; Paolo F Rinaudo; Joseph F Costello; Manish K Aghi; Emin Maltepe Journal: Cell Rep Date: 2015-02-13 Impact factor: 9.423
Authors: Kurosh Ameri; Anthony M Rajah; Vien Nguyen; Timothy A Sanders; Arman Jahangiri; Michael Delay; Matthew Donne; Hwa J Choi; Kathryn V Tormos; Yerem Yeghiazarians; Stefanie S Jeffrey; Paolo F Rinaudo; David H Rowitch; Manish Aghi; Emin Maltepe Journal: PLoS One Date: 2013-04-30 Impact factor: 3.240