Islet replacement via the Edmonton Protocol offers proof of concept that transient insulin independence can be achieved in patients with diabetes (1–4). However, the need for life-long immunosuppression, an extreme shortage of human islets, along with graft failure due to rejection and continued autoimmunity, limits the widespread application of this approach. Although recent progress has been made in the derivation of “ -like” cells from human pluripotent stem cell sources (embryonic stem cells or induced pluripotent stem cells) (5–10), inducing the replication of surviving -cells in situ (11, 12) and/or stimulating new islet formation from progenitor cells within the pancreas (islet neogenesis) (13–16) represents the most direct way to increase -cell mass. Studies in both rodents and humans suggest endogenous islet repair mechanisms may remain intact during diabetes and can be activated by cellor pharmacologically-mediated stimuli. Evidence of ongoing -cell regeneration has been observed in type 1 diabetes (T1D) patients at early onset (17) or many years after diagnosis (18). Indeed, recent analysis of T1D patients with disease duration of more than 50 years (medalists) has uncovered sustained c-peptide and proliferating -cells within the pancreas in the face of ongoing autoimmunity (19). Moreover, the increase in -cell mass in response to pregnancy suggests that the human endocrine pancreas has the capacity to regenerate if we can understand how to “tip the balance” in favor of islet regeneration vs destruction during diabetes. Interestingly, increased -cell replication was first suggested as the mechanism for increased -cell mass during pregnancy, but a recent autopsy study of human pancreases during pregnancy showed an increased proportion of small islets and increased number of insulin cells in the ducts but no change in -cell replication or apoptosis frequency (20). Nonetheless, novel strategies to optimize islet regeneration, either by stimulating -cell replication or by harnessing endogenous islet neogenic processes within the diabetic pancreas, remain under intense investigation for the treatment of diabetes. In initial publications documenting endogenous islet regeneration by stem cells, transplantation of bone marrow-derived c-kit cells reduced hyperglycemia in mice with streptozotocin (STZ)-induced -cell deletion (21). Importantly, transplanted stem cells did not acquire insulin expression as previously thought. In contrast, donor cells surrounded regenerating islets or engrafted in ductal regions and stimulated proliferation within recipient islets via undetermined paracrine activities (21). Subsequently, other preclinical and early clinical reports have shown that both human hematopoietic (22–26) or multipotent stromal cell (25–28), also known as mesenchymal stem cell (MSC) lineages, can enhance islet regeneration. Furthermore, islet regeneration and immune protection may be achieved by coinfusion of murine hematopoietic cells with MSC in autoimmune non-obese diabetic mice (29). Although this concept termed “stem cell-stimulated islet regeneration” has emerged as a central process for pancreas repair, either by stimulating -cell proliferation (11, 24– 26) or by initiating new islet formation from ductal or islet-derived precursors (14–16, 25, 26), the molecular signaling mechanisms by which distinct stem and progenitor cell types mediate islet recovery are not well understood. More importantly, recent controversy of the role of betatrophin in islet regeneration (30, 31) has underscored