Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury

Woochul Chang, Byeong Wook Song, Soyeon Lim, Heesang Song, ChiYoung Shim, Min Ji Cha, Hyuck Ahn Dong, Young Gook Jung, Dong Ho Lee, Hyung Chung Ji, Ki Doo Choi, Seung Kyou Lee, Namsik Chung, Sang Kyou Lee, Yangsoo Jang, Ki Chul Hwang

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Mesenchymal stem cell (MSC) therapy for myocardial injury has inherent limitations due to the poor viability of MSCs after cell transplantation. In this study, we directly delivered Hsp70, a protein with protective functions against stress, into MSCs, using the Hph-1 protein transduction domain ex vivo for high transfection efficiency and low cytotoxicity. Compared to control MSCs in in vitro hypoxic conditions, MSCs delivered with Hph-1-Hsp70 (Hph-1-Hsp70-MSCs) displayed higher viability and anti-apoptotic properties, including Bcl2 increase, reduction of Bax, JNK phosphorylation and caspase-3 activity. Hsp70 delivery also attenuated cellular ATP-depleting stress. Eight animals per group were used for in vivo experiments after occlusion of the left coronary artery. Transplantation of Hph-1-Hsp70-MSCs led to a decrease in the fibrotic heart area, and significantly reduced the apoptotic positive index by 19.5 ± 2%, compared to no-treatment controls. Hph-1-Hsp70-MSCs were well-integrated into the infarcted host myocardium. The mean microvessel count per field in the infarcted myocardium of the Hph-1-Hsp70-MSC-treated group (122.1 ± 13.5) increased relative to the MSC-treated group (75.9 ± 10.4). By echocardiography, transplantation of Hph-1-Hsp70-MSCs resulted in additional increases in heart function, compared to theMSCs-transplanted group. Our results may help formulate better clinical strategies for in vivo MSC cell therapy for myocardial damage.

Original languageEnglish
Pages (from-to)2283-2292
Number of pages10
JournalStem Cells
Volume27
Issue number9
DOIs
Publication statusPublished - 2009 Sep 1

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Mesenchymal Stromal Cells
Cell Death
Wounds and Injuries
Cell- and Tissue-Based Therapy
Myocardium
Proteins
Transplantation
Cell Transplantation
Microvessels
Caspase 3
Transfection
Echocardiography
Coronary Vessels
Adenosine Triphosphate
Phosphorylation
Hypoxia
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Chang, Woochul ; Song, Byeong Wook ; Lim, Soyeon ; Song, Heesang ; Shim, ChiYoung ; Cha, Min Ji ; Dong, Hyuck Ahn ; Jung, Young Gook ; Lee, Dong Ho ; Ji, Hyung Chung ; Choi, Ki Doo ; Lee, Seung Kyou ; Chung, Namsik ; Lee, Sang Kyou ; Jang, Yangsoo ; Hwang, Ki Chul. / Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury. In: Stem Cells. 2009 ; Vol. 27, No. 9. pp. 2283-2292.
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title = "Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury",
abstract = "Mesenchymal stem cell (MSC) therapy for myocardial injury has inherent limitations due to the poor viability of MSCs after cell transplantation. In this study, we directly delivered Hsp70, a protein with protective functions against stress, into MSCs, using the Hph-1 protein transduction domain ex vivo for high transfection efficiency and low cytotoxicity. Compared to control MSCs in in vitro hypoxic conditions, MSCs delivered with Hph-1-Hsp70 (Hph-1-Hsp70-MSCs) displayed higher viability and anti-apoptotic properties, including Bcl2 increase, reduction of Bax, JNK phosphorylation and caspase-3 activity. Hsp70 delivery also attenuated cellular ATP-depleting stress. Eight animals per group were used for in vivo experiments after occlusion of the left coronary artery. Transplantation of Hph-1-Hsp70-MSCs led to a decrease in the fibrotic heart area, and significantly reduced the apoptotic positive index by 19.5 ± 2{\%}, compared to no-treatment controls. Hph-1-Hsp70-MSCs were well-integrated into the infarcted host myocardium. The mean microvessel count per field in the infarcted myocardium of the Hph-1-Hsp70-MSC-treated group (122.1 ± 13.5) increased relative to the MSC-treated group (75.9 ± 10.4). By echocardiography, transplantation of Hph-1-Hsp70-MSCs resulted in additional increases in heart function, compared to theMSCs-transplanted group. Our results may help formulate better clinical strategies for in vivo MSC cell therapy for myocardial damage.",
author = "Woochul Chang and Song, {Byeong Wook} and Soyeon Lim and Heesang Song and ChiYoung Shim and Cha, {Min Ji} and Dong, {Hyuck Ahn} and Jung, {Young Gook} and Lee, {Dong Ho} and Ji, {Hyung Chung} and Choi, {Ki Doo} and Lee, {Seung Kyou} and Namsik Chung and Lee, {Sang Kyou} and Yangsoo Jang and Hwang, {Ki Chul}",
year = "2009",
month = "9",
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doi = "10.1002/stem.153",
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Chang, W, Song, BW, Lim, S, Song, H, Shim, C, Cha, MJ, Dong, HA, Jung, YG, Lee, DH, Ji, HC, Choi, KD, Lee, SK, Chung, N, Lee, SK, Jang, Y & Hwang, KC 2009, 'Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury', Stem Cells, vol. 27, no. 9, pp. 2283-2292. https://doi.org/10.1002/stem.153

Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury. / Chang, Woochul; Song, Byeong Wook; Lim, Soyeon; Song, Heesang; Shim, ChiYoung; Cha, Min Ji; Dong, Hyuck Ahn; Jung, Young Gook; Lee, Dong Ho; Ji, Hyung Chung; Choi, Ki Doo; Lee, Seung Kyou; Chung, Namsik; Lee, Sang Kyou; Jang, Yangsoo; Hwang, Ki Chul.

In: Stem Cells, Vol. 27, No. 9, 01.09.2009, p. 2283-2292.

Research output: Contribution to journalArticle

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T1 - Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury

AU - Chang, Woochul

AU - Song, Byeong Wook

AU - Lim, Soyeon

AU - Song, Heesang

AU - Shim, ChiYoung

AU - Cha, Min Ji

AU - Dong, Hyuck Ahn

AU - Jung, Young Gook

AU - Lee, Dong Ho

AU - Ji, Hyung Chung

AU - Choi, Ki Doo

AU - Lee, Seung Kyou

AU - Chung, Namsik

AU - Lee, Sang Kyou

AU - Jang, Yangsoo

AU - Hwang, Ki Chul

PY - 2009/9/1

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N2 - Mesenchymal stem cell (MSC) therapy for myocardial injury has inherent limitations due to the poor viability of MSCs after cell transplantation. In this study, we directly delivered Hsp70, a protein with protective functions against stress, into MSCs, using the Hph-1 protein transduction domain ex vivo for high transfection efficiency and low cytotoxicity. Compared to control MSCs in in vitro hypoxic conditions, MSCs delivered with Hph-1-Hsp70 (Hph-1-Hsp70-MSCs) displayed higher viability and anti-apoptotic properties, including Bcl2 increase, reduction of Bax, JNK phosphorylation and caspase-3 activity. Hsp70 delivery also attenuated cellular ATP-depleting stress. Eight animals per group were used for in vivo experiments after occlusion of the left coronary artery. Transplantation of Hph-1-Hsp70-MSCs led to a decrease in the fibrotic heart area, and significantly reduced the apoptotic positive index by 19.5 ± 2%, compared to no-treatment controls. Hph-1-Hsp70-MSCs were well-integrated into the infarcted host myocardium. The mean microvessel count per field in the infarcted myocardium of the Hph-1-Hsp70-MSC-treated group (122.1 ± 13.5) increased relative to the MSC-treated group (75.9 ± 10.4). By echocardiography, transplantation of Hph-1-Hsp70-MSCs resulted in additional increases in heart function, compared to theMSCs-transplanted group. Our results may help formulate better clinical strategies for in vivo MSC cell therapy for myocardial damage.

AB - Mesenchymal stem cell (MSC) therapy for myocardial injury has inherent limitations due to the poor viability of MSCs after cell transplantation. In this study, we directly delivered Hsp70, a protein with protective functions against stress, into MSCs, using the Hph-1 protein transduction domain ex vivo for high transfection efficiency and low cytotoxicity. Compared to control MSCs in in vitro hypoxic conditions, MSCs delivered with Hph-1-Hsp70 (Hph-1-Hsp70-MSCs) displayed higher viability and anti-apoptotic properties, including Bcl2 increase, reduction of Bax, JNK phosphorylation and caspase-3 activity. Hsp70 delivery also attenuated cellular ATP-depleting stress. Eight animals per group were used for in vivo experiments after occlusion of the left coronary artery. Transplantation of Hph-1-Hsp70-MSCs led to a decrease in the fibrotic heart area, and significantly reduced the apoptotic positive index by 19.5 ± 2%, compared to no-treatment controls. Hph-1-Hsp70-MSCs were well-integrated into the infarcted host myocardium. The mean microvessel count per field in the infarcted myocardium of the Hph-1-Hsp70-MSC-treated group (122.1 ± 13.5) increased relative to the MSC-treated group (75.9 ± 10.4). By echocardiography, transplantation of Hph-1-Hsp70-MSCs resulted in additional increases in heart function, compared to theMSCs-transplanted group. Our results may help formulate better clinical strategies for in vivo MSC cell therapy for myocardial damage.

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