Very small embryonic-like stem cells are involved in regeneration of mouse pancreas post-pancreatectomy

Introduction: Despite numerous research efforts, mechanisms underlying regeneration of pancreas remains controversial. Views are divided whether stem cells are involved during pancreatic regeneration or it involves duplication of pre-existing islets or ductal cells or whether pancreatic islet numbers are fixed by birth or they renew throughout life. Pluripotent embryonic stem (ES) and induced pluripotent stem (iPS) cells have been used by several groups to regenerate diabetic mouse pancreas but the beneficial effects are short-lived. It has been suggested that cells obtained after directed differentiation of ES/iPS cells resemble fetal and not their adult counterparts; thus are functionally different and may be of little use to regenerate adult pancreas. A novel population of pluripotent very small embryonic-like stem cells (VSELs) exists in several adult body tissues in both mice and humans. VSELs have been reported in the mouse pancreas, and nuclear octamer-binding transcription factor 4 (OCT-4) positive, small-sized cells have also been detected in human pancreas. VSELs are mobilized into peripheral blood in streptozotocin treated diabetic mice and also in patients with pancreatic cancer. This study aimed to evaluate whether VSELs are involved during regeneration of adult mouse pancreas after partial pancreatectomy. Methods: Mice were subjected to partial pancreatectomy wherein almost 70% of pancreas was surgically removed and residual pancreas was studied on Days 1, 3 and 5 post-surgery. Results: VSELs were detected in Hematoxylin and Eosin stained smears of pancreatic tissue as spherical, small sized cells with a large nucleus surrounded by a thin rim of cytoplasm and could be sorted as LIN-/CD45-/SCA-1+ cells by flow cytometry. Results reveal that although neutrophils with multi-lobed nuclei are mobilized into the pancreas on day 1 after pancreatectomy, by day 5 VSELs with spherical nuclei, high nucleo-cytoplasmic ratio and nuclear OCT-4 are mobilized into the residual pancreas. VSELs undergo differentiation and give rise to PDX-1 and OCT-4 positive progenitors which possibly regenerate both acinar cells and islets. Conclusions: Results provide direct evidence supporting the presence of VSELs in adult mouse pancreas and their role during regeneration. VSELs are an interesting alternative to ES/iPS cells to regenerate a diabetic pancreas in future.