Cardiac-derived stem cell engineered with constitutively active HIF-1α gene enhances blood perfusion of hindlimb ischemia

Xing Pei, Jiyoung Shin, Heejung Kim, Nana Wang, Chaewon Seo, Miyun Yoon, Xiongwen Chen, Jianqing Gao, Victor C. Yang, Huining He, Seungjin Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Stem cell-based therapeutic approach provides a possible treatment for critical limb ischemia (CLI) by inducing revascularization and regenerating ischemic tissue. However, the clinical benefit is modest due to low cell survival and limited efficacy after transplantation. Cardiac-derived stem cells (CSCs) might be a novel cell source for CLI treatment owing to their superb endothelial differentiation potential and angiogenic paracrine functions. In this study, the angiogenic ability of CSCs was maximized by genetic engineering with constitutively active form of hypoxia-inducible factor-1α (CA-HIF-1α), resistant to oxygen-dependent degradation. CSCs transfected with CA-HIF-1α (CA-HIF-CSCs) promoted supplementary expression of proangiogenic factors including VEGF, bFGF, Ang-1 and PDGF-B, along with enhanced angiogenic function including migratory effect, tube formation and endothelial differentiation potential. In the mouse CLI model, CA-HIF-CSCs transplanted into the ischemic region using fibrin gel as cell delivery vehicle, improved blood perfusion and limb functional recovery with minimal incidence of foot necrosis and limb loss by promoting new vessel formation. Histological evidence further confirmed that CA-HIF-CSC/gel treatment markedly alleviated muscle degeneration and fibrosis. CSCs genetically engineered with constitutively active HIF-1α provide a novel therapeutic modality in CLI combining stem cell and gene therapy.

Original languageEnglish
Pages (from-to)210-221
Number of pages12
JournalJournal of Industrial and Engineering Chemistry
Volume105
DOIs
StatePublished - 25 Jan 2022

Keywords

  • Cardiac-derived stem cell
  • Constitutively active hypoxia-inducible factor-1 α
  • Critical ischemia
  • Fibrin
  • Stem cell therapy

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