Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

Abstract

We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation 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 hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP bright CD45+ 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 dim CD45 − 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 synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.

Direct differentiation of bone marrow mononucleated cells into insulin producing cells using pancreatic β-cell-derived components

“…It has been previously reported that BMNCs significantly contribute to adult β-cell renewal in mice 27–31 , but other reports have contradicted these findings 32,33 . Initially, we tested whether BMNCs can differentiate into IPCs.…”

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

“…Finally, small embryonic-like bone marrow-derived HSC with a Fr25 linphenotype were shown to be most effective in infiltrating islets and aligning beside potential sites of β-cell neogenesis on pancreatic ducts in the diabetic mouse. 43 The precise signaling mechanisms responsible for initiation of β-cell proliferation by HSC are unknown, but there are a variety of potential target cells. In addition to a direct action on remaining but proliferatively quiescent β-cells, highly proliferative βcell progenitors have been identified in both the rodent and human pancreas.…”