The loss of insulin-producing β-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote β-cell proliferation, protection, and imaging. However, the lack of β-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in β-cells over other islet cells ex vivo or other cell-types in an organismal context will be immensely valuable in advancing diabetes research and therapeutic development. Here, we leverage the unusually high Zn(II) concentration in β-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to β-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in β-cells as compared to other pancreatic cells; importantly, Zn(II)-mediated hydrolysis triggers cargo activation. This prodrug system, with modular components that allow for fine-tuning selectivity, should enable the safer and more effective targeting of β-cells.
Human multipotent stromal cells (hMSC) can induce islet regeneration after transplantation via the secretion of proteins that establish an islet regenerative niche. However, the identity of hMSCsecreted signals and the mechanisms by which pancreatic islet regeneration is induced remain unknown. Recently, mammalian pancreatic α-cells have been shown to possess considerable plasticity, and differentiate into β-like cells after near complete β-cell loss or overexpression of key transcriptional regulators. These studies have generated new excitement that islet regeneration during diabetes may be possible if we can identify clinically applicable stimuli to modulate these key regulatory pathways. Herein, we demonstrate that intrapancreatic-injection of concentrated hMSC-conditioned media (CM) stimulated islet regeneration without requiring cell transfer. hMSC CM-injection significantly reduced hyperglycemia, increased circulating serum insulin concentration, and improved glucose tolerance in streptozotocin-treated mice. The rate and extent of endogenous β-cell mass recovery was dependent on total protein dose administered and was further augmented by the activation of Wnt-signaling using GSK3-inhibition during CM generation. Intrapancreatic hMSC CM-injection immediately set in motion a cascade of regenerative events that included the emergence of proliferating insulin + clusters adjacent to ducts, NKX6.1 expression in glucagon + cells at days 1-4 suggesting the acquisition of β-cell phenotype by α-cells, and accelerated β-cell maturation with increased MAFA-expression for >1 month postinjection. Discovery and validation of islet regenerative hMSC-secreted protein may lead to the development of cell-free regenerative therapies able to tip the balance in favor of β-cell regeneration versus destruction during diabetes. STEM CELLS 2019;37:516-528 SIGNIFICANCE STATEMENTCell-based therapies using human multipotent stromal cells (hMSC) to dampen autoimmunity while inducing islet regeneration represents a promising approach to treat diabetes. However, poor survival and retention of transplanted hMSC in the damaged pancreas complicates clinical translation. Here, it is demonstrated that hMSC secrete an array of islet-regenerative proteins and intrapancreatic delivery of hMSC-conditioned media (CM) could stimulate islet regeneration without the need for cell transfer. Wnt-pathway stimulated hMSC CM-injection set in motion a cascade of events consistent with the emergence of functional islets. Discovery of hMSC-secreted, islet-regenerative effectors may lead to the development of cell-free therapies to combat diabetes.
Highlights d The secretome of hMSCs contains unique signatures useful for potency analyses d Quantitative proteomics and machine learning predict b cell regenerative hMSCs d Secreted levels of IL-6 and CXCL8 are predictive of regenerative potency d Donor characteristics play an important role in the regenerative potency of hMSCs
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.