Augmentation of therapeutic augiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3β activity

Jin Ho Choi, Jin Hurt, Chang Hwan Yoon, Ji Hyun Kim, Choon Soo Lee, Seock Won Youn, Il Young Oh, Carsten Skurk, Toyoaki Murohara, Young Bae Park, Kenneth Walsh, Hyo Soo Kim

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Abstract

Previously we reported that inhibition of glycogen synthase kinase-3β (GSK3β), a key regulator in many intracellular signaling pathways, enhances the survival and migration of vascular endothelial cells. Here we investigated the effect of inhibition of GSK3β activity on the angiogenic function of endothelial progenitor cell (EPC) and demonstrated a new therapeutic angiogenesis strategy using genetically modified EPC. As we previously reported, two biologically distinct types of EPC, spindle-shaped "early EPC" and cobblestone-shaped "late EPC" could be cultivated from human peripheral blood. Catalytically inactive GSK3β gene was transduced into both EPC. Inhibition of GSK3β signaling pathway led to increased nuclear translocation of β-catenin and increased secretion of angiogenic cytokines (vascular endothelial growth factor and interleukin-8). It enhanced the survival and proliferation of early EPC, whereas it promoted the survival and differentiation of late EPC. Transplantation of either of these genetically modified EPC into the ischemic hind limb model of athymic nude mouse significantly improved blood flow, limb salvage, and tissue capillary density compared with nontransduced EPC. Inhibition of GSK3β signaling of either of these genetically modified EPC augmented the in vitro and in vivo angiogenic potency of these cell populations. These data provide evidence that GSK3β has a key role in the angiogenic properties of EPC. Furthermore, the genetic modification of EPC to alter this signaling step can improve the efficacy of cell-based therapeutic vasculogenesis.

Original languageEnglish (US)
Pages (from-to)49430-49438
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number47
DOIs
StatePublished - Nov 19 2004

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Glycogen Synthase Kinase 3
Endothelial cells
Therapeutics
Nude Mice
Endothelial Progenitor Cells
Survival
Blood
Catenins
Limb Salvage
Salvaging
Interleukin-8
Vascular Endothelial Growth Factor A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Augmentation of therapeutic augiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3β activity. / Choi, Jin Ho; Hurt, Jin; Yoon, Chang Hwan; Kim, Ji Hyun; Lee, Choon Soo; Youn, Seock Won; Oh, Il Young; Skurk, Carsten; Murohara, Toyoaki; Park, Young Bae; Walsh, Kenneth; Kim, Hyo Soo.

In: Journal of Biological Chemistry, Vol. 279, No. 47, 19.11.2004, p. 49430-49438.

Research output: Contribution to journalArticle

Choi, JH, Hurt, J, Yoon, CH, Kim, JH, Lee, CS, Youn, SW, Oh, IY, Skurk, C, Murohara, T, Park, YB, Walsh, K & Kim, HS 2004, 'Augmentation of therapeutic augiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3β activity', Journal of Biological Chemistry, vol. 279, no. 47, pp. 49430-49438. https://doi.org/10.1074/jbc.M402088200
Choi, Jin Ho ; Hurt, Jin ; Yoon, Chang Hwan ; Kim, Ji Hyun ; Lee, Choon Soo ; Youn, Seock Won ; Oh, Il Young ; Skurk, Carsten ; Murohara, Toyoaki ; Park, Young Bae ; Walsh, Kenneth ; Kim, Hyo Soo. / Augmentation of therapeutic augiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3β activity. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 47. pp. 49430-49438.
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