The role of genetically modified mesenchymal stem cells in urinary bladder regeneration

Devon C. Snow-Lisy, Edward C. Diaz, Matthew I. Bury, Natalie J. Fuller, Jessica H. Hannick, Nida Ahmad, Arun K. Sharma

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stemprogenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, themolecular pathways governing these events are unknown. The pleiotropic effects ofWnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration.Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-expressWnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentationmodel. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/ mm2) and bladder smoothmuscle content (~42%vs ~36%) in Cyr61OX (over-expressing) vs Cyr61KD (knock-down) groups. Muscle content decreased to ~25%at 10 weeks in Cyr61KD groups.Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/ mm2 and ~51%, respectively) at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX andWnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate thatMSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation.Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation ofMSCs with CD34+ HSPCs and may be specifically targeted as an alternate means to achieve functional bladder regeneration.

Original languageEnglish (US)
Article numbere0138643
JournalPloS one
Volume10
Issue number9
DOIs
StatePublished - Sep 23 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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