title: Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration.
abstract: OBJECTIVE
  We sought to investigate the stimulation of islet regeneration by transplanted human umbilical cord blood (UCB) cells purified according to high aldehyde dehydrogenase (ALDH) activity (ALDH(hi)), a conserved characteristic of multiple progenitor lineages. We hypothesised that direct intrapancreatic (iPan) delivery of ALDH(hi) progenitors would augment islet regeneration via timely and localised exposure to islet-regenerative stimuli.
  
  
  METHODS
  Cells were purified from UCB based on flow cytometry for low ALDH activity (ALDH(lo)) vs ALDH(hi). UCB ALDH(lo) or ALDH(hi) cells were compared for surface marker expression, as well as haematopoietic, endothelial and multipotent stromal progenitor content in vitro. UCB ALDH(lo) or ALDH(hi) cells were i.v. or iPan injected into streptozotocin-treated non-obese diabetic/severe combined immune-deficient mice temporally monitored for blood glucose, serum insulin and glucose tolerance. Human cell recruitment and survival in the pancreas, insulin content, islet-associated cell proliferation and islet vascularisation were documented in situ.
  
  
  RESULTS
  UCB-derived ALDH(hi) cells were highly enriched for haematopoietic and endothelial progenitor frequency, and showed increased expression of progenitor and myeloid cell surface markers. Although i.v. transplantation of ALDH(hi) cells demonstrated low pancreas engraftment and only transient blood glucose lowering capacity, iPan injected ALDH(hi) cells reversed established hyperglycaemia, increased serum insulin and improved the response to a glucose challenge. iPan injected ALDH(hi) cells surrounded damaged islets at early time points and increased islet-associated cell proliferation, resulting in the recovery of beta cell mass.
  
  
  CONCLUSIONS
  iPan delivery of UCB ALDH(hi) cells potentiated islet-associated cell proliferation, insulin production and islet revascularisation, resulting in the recovery of host islet function. Elucidation of the progenitor-specific pathways stimulated during islet regeneration may provide new approaches to promote islet expansion during diabetes.
authors.affiliation: Program in Regenerative Medicine, Krembil Centre for Stem Cell Biology, Vascular Biology Group, Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, PO Box 5015, 100 Perth Drive, London, ON, Canada N6A 5K8.
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: D M
authors.initials: DM
authors.lastname: Putman
authors.forename: J M
authors.initials: JM
authors.lastname: Hughes-Large
authors.forename: D A
authors.initials: DA
authors.lastname: Hess
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D012038:Regeneration / Q000235:genetics / Q000502:physiology*
chemical_list: D000444:Aldehyde Dehydrogenase