What question did this study set out to answer?

This research aims to discover and validate specific proteins secreted by human multipotent stromal cells that promote islet regeneration.

May 1, 2026

Discovery and validation of islet regenerative proteins secreted by human multipotent stromal cells.

Key Points

This research aims to discover and validate specific proteins secreted by human multipotent stromal cells that promote islet regeneration.
Utilized mass spectrometry-based proteomic analyses to compare Wnt-activated vs untreated MSC secretomes.
Conducted iPan injections of identified proteins in streptozotocin-treated NOD/SCID mice and assessed various metabolic parameters.
Evaluated outcomes at 4- and 32-days post-treatment, focusing on glucose and islet function.
Identified eight proteins associated with islet regeneration, including CALU and SOD1.
Single iPan injection of the 8-protein combination significantly lowered hyperglycemia and improved glucose tolerance.
CALU and SOD1 improved glucose tolerance and reduced nonfasting glucose levels.

Abstract

INTRODUCTION: Diabetes affects >500 million people worldwide. Despite insulin therapy, most patients develop devastating complications, emphasizing the need for curative strategies. Human multipotent stromal/stem cells (MSC) secrete factors that promote islet regeneration. We previously showed that intrapancreatic (iPan) delivery of Wnt-activated MSC-conditioned media (Wnt+ CM) stimulates islet regeneration without cell transfer. This study aimed to identify and functionally validate specific MSC-secreted proteins with islet regenerative potential. METHODS: Comprehensive mass spectrometry-based, quantitative proteomic analyses comparing Wnt-pathway activated versus untreated MSC secretomes were cross-referenced with a prior dataset distinguishing regenerative from nonregenerative MSC CM. Proteins enriched in both conditions were iPan-injected individually or in combination into streptozotocin-treated NOD/SCID mice. Nonfasting glucose, glucose tolerance, beta cell mass, islet morphology, and islet cell proliferation were assessed at 4- and 32-days post-treatment. RESULTS: Cross-referenced secretome analyses identified eight proteins implicated in islet regeneration: CALU, CTSB, FAM3C, GAL1, PPIA, PSAP, SOD1, and TGM2. A single iPan-injection of the 8-protein combination significantly lowered hyperglycemia, improved glucose tolerance, and increased beta cell mass, comparable to Wnt+ CM. Regenerative effects such as increased beta cell proliferation appeared as early as day 4. Single-protein testing identified CALU and SOD1 as leading candidates, improving glucose tolerance and reducing nonfasting glucose. CONCLUSION: This study defines a set of MSC-secreted proteins that promote islet regeneration in vivo, supporting the development of protein-based biologics to preserve or restore beta cell function during diabetes, with potential applications alongside islet replacement therapies to enhance graft survival and function.

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