Lineage tracing and resulting phenotype of haemopoietic-derived cells in the pancreas during beta cell regeneration.
OBJECTIVE
Transplantation of bone marrow-derived haemopoietic stem cells following streptozotocin (STZ) treatment to induce pancreatic beta cell loss in mice causes the partial regeneration of beta cell mass, with many haemopoietic cells demonstrating endothelial cell markers. This study used genetically tagged haemopoietic lineage-derived cells to determine how endogenous cells are mobilised following beta cell loss and subsequent replacement.


METHODS
A double transgenic mouse model, Vav-iCre; R26R-enhanced yellow fluorescent protein (YFP), was used where only haemopoietic lineage cells expressed the Vav1 gene promoter allowing expression of the YFP reporter gene. Between postnatal days 2 and 4 mice were injected with STZ or vehicle (control) and body weight and glycaemia were monitored. Mice were killed between days 10 and 130, and the pancreases were examined by immunofluorescence microscopy.


RESULTS
YFP-expressing cells infiltrated the pancreas at all ages, being present around newly forming islets at the pancreatic ducts, and within larger islets. Small numbers of YFP-positive cells (<5%) co-stained for the macrophage markers F4/80 or Mac1, for cytokeratin 19, or for the transcription factor pancreatic and duodenal homeobox 1 (PDX-1), but no co-localisation was seen with insulin or other endocrine hormones. Within islets approximately 30% of YFP-positive cells co-stained for the endothelial cell marker CD31, and following STZ the number of haemopoietic-derived cells, and the proportion that were CD31-positive, both significantly increased after 21 and 40 days, coincident with a partial replacement of beta cells.


CONCLUSIONS
Our results suggest that following beta cell loss endogenous haemopoietic-lineage cells contribute to intra-islet angiogenesis, which supports a partial recovery of beta cell mass.
Chamson-Reig
A
A
Lawson Health Research Institute, St Joseph's Health Care, 268 Grosvenor Street, London, ON, Canada N6A 4V2.
Arany
E J
EJ
Hill
D J
DJ
D000704:Analysis of Variance; D000818:Animals; D019070:Cell Lineage / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D005455:Fluorescent Antibody Technique; D018380:Hematopoietic Stem Cell Transplantation; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*