Insulin‐Like Growth Factor Promotes Engraftment, Differentiation, and Functional Improvement after Transfer of Embryonic Stem Cells for Myocardial Restoration

Kofidis, Theo; Bruin, Jorg L. de; Yamane, Toshiyuki; Balsam, Leora B.; Lebl, Darren R.; Swijnenburg, Rutger-Jan; Tanaka, Masashi; Weissman, Irving L.; Robbins, Robert C.

doi:10.1634/stemcells.2004-0127

Cited by 123 publications

(74 citation statements)

References 26 publications

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“…44 IGF-1 promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration. 16 Urbanek and coworkers found that resident cardiac stem cells express the IGF-1R, 15 and our present data demonstrate expression of a functionally active IGF-1R in EPC. ϩ -derived EPC, freshly isolated CD133 ϩ / VEGFR2 ϩ EPC and rescue of impaired function of EPC derived from elderly subjects by IGF-1.…”

Section: Thum Et Al Igf-1 Corrects Impairment Of Epc 439supporting

confidence: 73%

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Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1

Thum

Hoeber

Froese

et al. 2007

Circulation Research

268

198

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Abstract-Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4Ϯ1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5Ϯ0.9 and 74.1Ϯ0.9 years). Middle-aged and elderly subjects had lower circulating CD133 ϩ /VEGFR-2 ϩ EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0Ϯ7.2 ng/mL versus 241.1Ϯ13.8 ng/mL; PϽ0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC. Patients with reduced EPC levels are at increased risk for cardiovascular events and death. 3,4 Recent studies suggest augmentation of circulating EPC to result in improved coronary collateral development in coronary artery disease. 5 Increasing age is associated with decreased number 6 and impaired function of EPC, 7 which may facilitate atherosclerotic processes. Regulation of EPC mobilization, differentiation and function is complex, but specific growth hormones and cytokines are explicitly involved. 8 Insulin-like growth factor-1 (IGF-1) enhances migration, tube formation and angiogenesis of mature endothelial cells 9 and increases te- Low serum IGF-1 levels, common in the elderly, are associated with an increased risk for ischemic heart disease. 12 Restoration of IGF-1 in elderly individuals by growth hormone therapy may have significant beneficial health effects. 13 In growth hormone de...

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Section: Thum Et Al Igf-1 Corrects Impairment Of Epc 439supporting

confidence: 73%

“…15 Likewise, in the infarcted myocardium, IGF-1 promotes engraftment, differentiation, and function of implanted embryonic stem cells leading to improved myocardial function. 16 IGF-1 transgenic mice demonstrate increased telomerase activity and preservation of cardiac resident stem cells. 10 The effects of IGF-1 on EPC homeostasis and function are not known.…”

mentioning

confidence: 99%

Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1

Thum

Hoeber

Froese

et al. 2007

Circulation Research

268

198

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“…In view of the risks associated with the broad differentiation potential of ESCs in vivo, only sporadic reports employed these cells in their uncommitted state to repair the damaged heart (203,243,244,312,313,509). In sharp contrast to the pluripotency of ESCs, cardiomyocytes were detected, but capillary structures and resistance arterioles were not found.…”

Section: A Human Embryonic Stem Cellsmentioning

confidence: 99%

Cardiac Stem Cells and Mechanisms of Myocardial Regeneration

Leri

Kajstura²,

Anversa³

2005

Physiological Reviews

397

349

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This review discusses current understanding of the role that endogenous and exogenous progenitor cells may have in the treatment of the diseased heart. In the last several years, a major effort has been made in an attempt to identify immature cells capable of differentiating into cell lineages different from the organ of origin to be employed for the regeneration of the damaged heart. Embryonic stem cells (ESCs) and bone marrow-derived cells (BMCs) have been extensively studied and characterized, and dramatic advances have been made in the clinical application of BMCs in heart failure of ischemic and nonischemic origin. However, a controversy exists concerning the ability of BMCs to acquire cardiac cell lineages and reconstitute the myocardium lost after infarction. The recognition that the adult heart possesses a stem cell compartment that can regenerate myocytes and coronary vessels has raised the unique possibility to rebuild dead myocardium after infarction, to repopulate the hypertrophic decompensated heart with new better functioning myocytes and vascular structures, and, perhaps, to reverse ventricular dilation and wall thinning. Cardiac stem cells may become the most important cell for cardiac repair.

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“…IGF-1 overexpression increases cardiac stem cell number and growth, leading to an increase in myocyte turnover and function in the aging heart (6). After infarction, IGF-1 promotes engraftment, differentiation, and functional improvement of embryonic stem cells transplanted into myocardium (7). However, IGF-1 is a small protein that diffuses readily through tissues, a property that allows it to signal over great distances (8), but this property could restrict its retention within a tissue for prolonged periods.…”

mentioning

confidence: 99%

Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

Davis

Hsieh²,

Takahashi³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

559

411

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Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a ''biotin sandwich'' approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy.engineering ͉ maturation ͉ scaffold

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Insulin‐Like Growth Factor Promotes Engraftment, Differentiation, and Functional Improvement after Transfer of Embryonic Stem Cells for Myocardial Restoration

Cited by 123 publications

References 26 publications

Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1

Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1

Cardiac Stem Cells and Mechanisms of Myocardial Regeneration

Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

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