Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

Andrew R. Kompa; David W. Greening; Anne M. Kong; Paul J. McMillan; Haoyun Fang; Ritika Saxena; Raymond C.B. Wong; Jarmon G. Lees; Priyadharshini Sivakumaran; Andrew E. Newcomb; Bakhos A. Tannous; Cameron Kos; Lina Mariana; Thomas Loudovaris; Derek J. Hausenloy; Shiang Y. Lim

doi:10.1093/cvr/cvaa088

Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

Andrew R. Kompa, David W. Greening, Anne M. Kong, Paul J. McMillan, Haoyun Fang, Ritika Saxena, Raymond C.B. Wong, Jarmon G. Lees, Priyadharshini Sivakumaran, Andrew E. Newcomb, Bakhos A. Tannous, Cameron Kos, Lina Mariana, Thomas Loudovaris, Derek J. Hausenloy, Shiang Y. Lim

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.

Original language	English (US)
Pages (from-to)	918-929
Number of pages	12
Journal	Cardiovascular research
Volume	117
Issue number	3
DOIs	https://doi.org/10.1093/cvr/cvaa088
State	Published - Mar 1 2021
Externally published	Yes

Keywords

Cardiac remodelling
Cardiac stem cells
Heart failure
Myocardial infarction
Secretome
TheraCyte

ASJC Scopus subject areas

General Medicine

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10.1093/cvr/cvaa088

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Kompa, A. R., Greening, D. W., Kong, A. M., McMillan, P. J., Fang, H., Saxena, R., Wong, R. C. B., Lees, J. G., Sivakumaran, P., Newcomb, A. E., Tannous, B. A., Kos, C., Mariana, L., Loudovaris, T., Hausenloy, D. J., & Lim, S. Y. (2021). Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction. Cardiovascular research, 117(3), 918-929. https://doi.org/10.1093/cvr/cvaa088

Kompa, AR, Greening, DW, Kong, AM, McMillan, PJ, Fang, H, Saxena, R, Wong, RCB, Lees, JG, Sivakumaran, P, Newcomb, AE, Tannous, BA, Kos, C, Mariana, L, Loudovaris, T, Hausenloy, DJ & Lim, SY 2021, 'Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction', Cardiovascular research, vol. 117, no. 3, pp. 918-929. https://doi.org/10.1093/cvr/cvaa088

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title = "Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction",

abstract = "Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.",

keywords = "Cardiac remodelling, Cardiac stem cells, Heart failure, Myocardial infarction, Secretome, TheraCyte",

author = "Kompa, {Andrew R.} and Greening, {David W.} and Kong, {Anne M.} and McMillan, {Paul J.} and Haoyun Fang and Ritika Saxena and Wong, {Raymond C.B.} and Lees, {Jarmon G.} and Priyadharshini Sivakumaran and Newcomb, {Andrew E.} and Tannous, {Bakhos A.} and Cameron Kos and Lina Mariana and Thomas Loudovaris and Hausenloy, {Derek J.} and Lim, {Shiang Y.}",

year = "2021",

month = mar,

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doi = "10.1093/cvr/cvaa088",

language = "English (US)",

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journal = "Cardiovascular research",

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T1 - Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

AU - Kompa, Andrew R.

AU - Greening, David W.

AU - Kong, Anne M.

AU - McMillan, Paul J.

AU - Fang, Haoyun

AU - Saxena, Ritika

AU - Wong, Raymond C.B.

AU - Lees, Jarmon G.

AU - Sivakumaran, Priyadharshini

AU - Newcomb, Andrew E.

AU - Tannous, Bakhos A.

AU - Kos, Cameron

AU - Mariana, Lina

AU - Loudovaris, Thomas

AU - Hausenloy, Derek J.

AU - Lim, Shiang Y.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.

AB - Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.

KW - Cardiac remodelling

KW - Cardiac stem cells

KW - Heart failure

KW - Myocardial infarction

KW - Secretome

KW - TheraCyte

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Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

Abstract

Keywords

ASJC Scopus subject areas

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