Abstract
Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.
Highlights
Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes
12-days post-transplantation, the proportion of proliferating beta cells, both counting cells positive for the proliferation marker ki[67] or for the marker of cellular mitosis phosho-histone H3 (pHH3), were higher in the grafts implanted in p16 relative to 20wo recipients (Fig. 1a–c)
Similar to their mouse counterparts, human beta cells proliferated more when transplanted into young relative to adult mouse recipients (Fig. 1d–f). These experiments support the notion that the young circulatory systemic environment stimulates the proliferation of adult mouse and human beta cells
Summary
Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Loss of islet responsiveness to platelet-derived growth factor (PDGF) signaling due to downregulation of the expression of PDGF receptors has been associated to the decline in beta cell proliferation after birth[3] As it has been shown for other cell types, the age-dependent decrease in beta cell proliferation depends on intrinsic molecular changes, but it is the consequence of modifications of the systemic environment that cells are exposed to[4,5,6]. There are six CCN proteins, designated CCN1 to CCN6, which share a modular structure comprised of a signal peptide followed by three domains with homology to insulin-like growth factor binding protein, von Willebrand type C and thrombospondin type 1 repeat, plus a fourth domain which contains a cysteine-knot motif[14] This modular structure underlies the pleiotropic functions and cell-specific behavior of this family of proteins, as CCN proteins can use different cell-surface receptors in different cell types to interact with multiple partners present in the surrounding extracellular matrix[15]. CCN2/CTGF is expressed in mouse embryonic beta cells and re-expressed in adult beta cells during periods of expansion such as pregnancy or after high fat feeding[17]
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