Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization

Area of Science:

• Cell Biology
• Regenerative Medicine
• Endocrinology

Background:

• Transplanted murine bone marrow (BM) progenitor cells can recruit to injured pancreases and stimulate endogenous beta cell proliferation, enhancing islet function.
• Identifying analogous human progenitor cell types is crucial for stimulating islet regeneration and treating diabetes.

Purpose of the Study:

• To investigate the potential of human bone marrow (BM)-derived progenitor cells, specifically those with high aldehyde dehydrogenase activity (ALDH(hi)), to promote islet regeneration.
• To compare the regenerative capacities of uncultured ALDH(hi) mixed progenitor cells versus culture-expanded, ALDH-purified multipotent stromal cells (MSCs) in a mouse model of diabetes.

Main Methods:

• Human BM was purified based on high aldehyde dehydrogenase activity (ALDH(hi)).
• Two types of cells were transplanted into streptozotocin-treated NOD/SCID mice: uncultured ALDH(hi) mixed progenitor cells and culture-expanded, ALDH-purified MSC subsets.
• Systemic hyperglycemia, insulin secretion, islet size, vascularization, beta cell mass, and proliferation markers were assessed.

Main Results:

• Intravenous injection of uncultured BM ALDH(hi) cells improved hyperglycemia and insulin secretion by increasing islet size and vascularization, without altering total islet number.
• These cells induced islet-specific proliferative and pro-angiogenic programs.
• Transplantation of ALDH-purified MSCs reduced hyperglycemia and augmented beta cell mass by promoting ductal-associated beta cell clusters, without increasing vascularization or activating Ngn3(+) endocrine precursors.

Conclusions:

• Endogenous islet recovery following progenitor cell transplantation can be achieved through distinct mechanisms, influenced by the specific progenitor cell subtypes used.
• Understanding how specific progenitor subsets activate islet regenerative and pro-angiogenic programs is key for developing novel combination cellular therapies for diabetes.