Bone Marrow Transplantation Temporarily Improves Pancreatic Function in Streptozotocin-Induced Diabetes: Potential Involvement of Very Small Embryonic-Like Cells

Abstract

BACKGROUND The role of bone marrow (BM)-derived cells in pancreatic β-cell regeneration remains unresolved. Here we examined whether BM-derived cells are recruited to the site of moderate pancreatic injury and contribute to β-cell regeneration. METHODS Low-dose streptozotocin (STZ) treatment was utilized to induce moderate pancreatic damage and hyperglycemia. Enhanced green fluorescent protein-positive (EGFP+) BM chimeras were evaluated for β-cell regeneration after STZ treatment. RESULTS To test the hypothesis that pancreatic tissue injury induces an SDF-1 gradient to chemoattract the stem cells, we evaluated the expression of mRNA for SDF-1 in damaged pancreatic tissue. SDF-1 was significantly increased in the pancreas after damage, peaking day 10. The majority of BM cells expressing mRNA for pancreatic development markers were detected in the subpopulation of CD45−/Sca-1+/Lin− very small embryonic-like (VSEL) cells. VSEL cells mobilized from BM to peripheral blood (PB) in response to pancreatic damage, peaking in PB at day 5, and were highly enriched in the pancreas 10–15 days after STZ treatment. To confirm a role for BM-derived cells in pancreatic β-cell regeneration, we prepared EGFP+→ B6 chimeras. In the EGFP+ chimeras, EGFP+ cells were detected around duct and islets and were positive for insulin after STZ treatment. However, STZ-induced hyperglycemia was reduced only transiently (49 to 77 days) after pancreatic injury. CONCLUSIONS These data suggest that VSEL cells are mobilized into injured pancreatic tissue and contribute to β-cell regeneration. Transplantation of BM-derived cells improves the function of injured pancreas, although the response is not sufficient to restore sustained normoglycemia.

Pluripotent Stem Cells in Bone Marrow and Cord Blood

“…Their presence amongst the MSCs in the Wharton's jelly is in agreement with observations made by other groups that MSCs contain a sub-population of more primitive stem cells [52] or even as postulated by Taichman and group [53] that VSELs are precursors of MSCs. Various studies have also reported that VSELs are mobilized into peripheral blood in response to injury/ stress in animal models [27,[54][55][56] as well as in humans [28][29][30]57] -thus suggesting a role in regeneration and homeostasis.…”

Nutritional programming of pancreatic β-cell plasticity

“…The ability of such cells to selectively home to damaged tissues has been variously linked to their expression of L-selectin [50] , β2-integrins [51] and stromal cell-derived factor-1 [52] . In some studies, a direct trans-differentiation of bone marrow-, a direct trans-differentiation of bone marrowa direct trans-differentiation of bone marrowderived stem cells into insulin-positive β-cells was demonstrated, either in vivo or following in vitro lineage manipulation [53][54][55] but the direct contribution of bone marrow stem cells to new β-cells has generally been found to be low and inconsistent with the resulting increase in insulin secretion and/or normalization of blood glucose [46,[56][57][58] .…”

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

“…Controversial evidence on neogenesis of insulinproducing cells has been presented by studies using hematopoietic progenitor markers such as SCA-1 and ckit, ranging from positive identification of differentiation (22,46) to negative results (19,68). The positive identification of Fr25lin − cell conversion to produce insulin (24) was used to address the possible use of these markers for prospective identification of the candidate stem cells that participate in islet regeneration.…”

“…This established model (8,14,19,22,24,25,40,64,68) includes selective injury by five consecutive doses of 60 mg/g STZ (days −6 to −2) followed by sublethal irradiation (675 rad) and cell grafting after 1 day (Fig. 2A).…”

“…On the one hand, murine cells derived from the bone marrow (23) and spleen (36) and human UCB cells (21) incorporate in the islets of irradiated recipients, as also observed after UCB cell grafting in neonate immunodeficient mice (69). Insulin production has been detected in particular subsets of stem cells after islet injury (36,46): very small embryonic-like (VSEL) cells corresponding to a cluster of differentiation 45-negative stem cell antigen 1 (lymphocyte antigen 6 complex, locus A; Ly6a)-positive chemokine C-X-C motif receptor 4-positive lineage-negative (CD45 − SCA-1 + CXCR4 + lin − ) phenotype (22,55) and small-sized elutriated cells (elutriated flow rate 25 ml/min; Fr25) devoid of lineage markers (Fr25lin − ) (24). Altogether these data suggest that neogenesis of insulin-producing cells is a rather low-efficiency mechanism of islet repair, provided that the autoimmune reaction is controlled or abrogated (26).…”