Hypoxia-induced therapeutic neovascularization in a mouse model of an ischemic limb using cell aggregates composed of HUVECs and cbMSCs

Chieh Cheng Huang, Ding Yuan Chen, Hao Ji Wei, Kun Ju Lin, Cheng Tse Wu, Ting Yin Lee, Hsin Yi Hu, Shiaw Min Hwang, Yen Chang, Hsing Wen Sung*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

34 Scopus citations

Abstract

Cell transplantation for therapeutic neovascularization holds great promise for treating ischemic diseases. This work prepared three-dimensional aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs) with different levels of internal hypoxia by a methylcellulose hydrogel system. We found that few apoptosis occurred in these cell aggregates, despite developing a hypoxic microenvironment in their inner cores. Via effectively switching on the hypoxia-inducible factor-1α-dependent angiogenic mechanisms, culturing the internally hypoxic HUVEC/cbMSC aggregates on Matrigel resulted in formation of extensive and persistent tubular networks and significant upregulation of pro-angiogenic genes. As the level of internal hypoxia created in cell aggregates increased, the robustness of the tubular structures developed on Matrigel increased, and expression levels of the pro-angiogenic genes also elevated. Transplantation of hypoxic HUVEC/cbMSC aggregates into a mouse model of an ischemic limb significantly promoted formation of functional vessels, improved regional blood perfusion, and attenuated muscle atrophy and bone losses, thereby rescuing tissue degeneration. Notably, their therapeutic efficacy was clearly dependent upon the level of internal hypoxia established in cell aggregates. These analytical results demonstrate that by establishing a hypoxic environment in HUVEC/cbMSC aggregates, their potential for therapeutic neovascularization can be markedly enhanced.

Original languageEnglish
Pages (from-to)9441-9450
Number of pages10
JournalBiomaterials
Volume34
Issue number37
DOIs
StatePublished - 12 2013

Keywords

  • Cell transplantation
  • Cell-based therapy
  • Hypoxia-inducible factors
  • Tissue engineering
  • Tissue ischemia

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