Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

Arman T. Askari; Samuel Unzek; Zoran B. Popovic; Corey K. Goldman; Farhad Forudi; Matthew Kiedrowski; Aleksandr Rovner; Stephen G. Ellis; James D. Thomas; Paul E. DiCorleto; Eric J. Topol; Marc S. Penn

doi:10.1016/S0140-6736(03)14232-8

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

Arman T. Askari, Samuel Unzek, Zoran B. Popovic, Corey K. Goldman, Farhad Forudi, Matthew Kiedrowski, Aleksandr Rovner, Stephen G. Ellis, James D. Thomas, Paul E. DiCorleto, Eric J. Topol, Marc S. Penn^*

^*Corresponding author for this work

Medicine, Cardiology Division

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

1131 Scopus citations

Abstract

Background: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. Methods: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. Findings: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm², n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). Interpretation: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

Original language	English (US)
Pages (from-to)	697-703
Number of pages	7
Journal	Lancet
Volume	362
Issue number	9385
DOIs	https://doi.org/10.1016/S0140-6736(03)14232-8
State	Published - Aug 30 2003

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10.1016/S0140-6736(03)14232-8

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@article{3f0b5fa8ee8d46fd9442f63677a6801e,

title = "Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy",

abstract = "Background: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. Methods: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. Findings: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). Interpretation: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.",

author = "Askari, {Arman T.} and Samuel Unzek and Popovic, {Zoran B.} and Goldman, {Corey K.} and Farhad Forudi and Matthew Kiedrowski and Aleksandr Rovner and Ellis, {Stephen G.} and Thomas, {James D.} and DiCorleto, {Paul E.} and Topol, {Eric J.} and Penn, {Marc S.}",

note = "Funding Information: We thank Jeanne Drinko for her expert echocardiographic skills. ATA is a recipient of the Vascular Biology Working Group Research Award and an American Heart Association, Ohio Valley Affiliate, Post-Doctoral Fellowship Award. This work was supported by NASA NCC 9-58, Houston, TX, and equipment grants from GE Medical (Milwaukee, WI) and Siemens Medical Systems (Mountain View, CA).",

year = "2003",

month = aug,

day = "30",

doi = "10.1016/S0140-6736(03)14232-8",

language = "English (US)",

volume = "362",

pages = "697--703",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "9385",

}

TY - JOUR

T1 - Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

AU - Askari, Arman T.

AU - Unzek, Samuel

AU - Popovic, Zoran B.

AU - Goldman, Corey K.

AU - Forudi, Farhad

AU - Kiedrowski, Matthew

AU - Rovner, Aleksandr

AU - Ellis, Stephen G.

AU - Thomas, James D.

AU - DiCorleto, Paul E.

AU - Topol, Eric J.

AU - Penn, Marc S.

N1 - Funding Information: We thank Jeanne Drinko for her expert echocardiographic skills. ATA is a recipient of the Vascular Biology Working Group Research Award and an American Heart Association, Ohio Valley Affiliate, Post-Doctoral Fellowship Award. This work was supported by NASA NCC 9-58, Houston, TX, and equipment grants from GE Medical (Milwaukee, WI) and Siemens Medical Systems (Mountain View, CA).

PY - 2003/8/30

Y1 - 2003/8/30

N2 - Background: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. Methods: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. Findings: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). Interpretation: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

AB - Background: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. Methods: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. Findings: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). Interpretation: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

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U2 - 10.1016/S0140-6736(03)14232-8

DO - 10.1016/S0140-6736(03)14232-8

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JO - The Lancet

JF - The Lancet

IS - 9385

ER -

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

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