Two distinct mechanisms mediate the involvement of bone marrow cells in islet remodeling: Neogenesis of insulin-producing cells and support of islet recovery

We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutri-ation and depleted of lineage markers (Fr25lin^-) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hema-topoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP^brightCD45⁺ progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin^- cells incorporate in the islets, convert to GFP^dimCD45^-PDX-1⁺ phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin^- cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two syn-ergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.