title: The Role of Genetically Modified Mesenchymal Stem Cells in Urinary Bladder Regeneration.
abstract: Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stem progenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a 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-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2) and bladder smooth muscle 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 and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-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 of MSCs with CD34+ HSPCs and may be specifically targeted as an alternate means to achieve functional bladder regeneration.
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America.
authors.forename: Devon C
authors.initials: DC
authors.lastname: Snow-Lisy
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Diaz
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Bury
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Fuller
authors.affiliation: Department of Urology, Loyola University Health System, Maywood, IL, United States of America.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Hannick
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America.
authors.forename: Nida
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Division of Pediatric Urology, Chicago, IL, United States of America; Northwestern University Feinberg School of Medicine, Department of Urology, Chicago, IL, United States of America; Northwestern University, Simpson Querrey Institute for BioNanotechnology, Chicago, IL, United States of America; Northwestern University, Department of Biomedical Engineering, Evanston, IL, United States of America.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D055515:Cysteine-Rich Protein 61 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009416:Nerve Regeneration; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D012038:Regeneration / Q000502:physiology*; D023822:Tissue Engineering; D001743:Urinary Bladder / Q000502:physiology*; D014563:Urodynamics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D018952:Antigens, CD34; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein