Schornack, Anna Marie

Stem cell-derived β (SC-β) cells are a promising therapy for type 1 diabetes (T1D), but their long-term efficacy is limited by immune-mediated graft rejection. Platelet-derived exosome product (PEP) has emerged as a novel immunomodulatory agent, although its effect on SC-β cell xenograft rejection remains unclear. Here, we evaluated PEP in stimulated human peripheral blood mononuclear cells (PBMCs) and in an immunocompetent mouse model of SC-β cell transplantation under the kidney capsule. Immune-related gene expression was assessed by quantitative PCR, immune cell infiltration by immunofluorescence, and graft function by circulating human insulin. In vitro, PEP reduced NK-cell-associated gene expression, including NK1.1, EOMES, and KLRK1, and increased IL-10 expression. In vivo, untreated SC-β cell xenografts showed progressive immune infiltration and loss of detectable human insulin by day 14, whereas PEP-treated grafts retained detectable insulin through day 14 across co-transplantation, pretreatment, and systemic administration strategies. PEP co-transplantation delayed, but did not prevent, xenograft rejection, with graft loss observed by day 21. This delay was associated with reduced NK1.1+ cell infiltration and lower expression of selected inflammatory and rejection-associated markers, including NK1.1, Nos2, and Nlrp3. These findings suggest that PEP modulates graft-associated immune responses and may serve as an adjunct immunomodulatory strategy for stem cell-based therapies for type 1 diabetes. Further studies are needed to evaluate sustained graft durability, safety, and translational efficacy.

Directed differentiation protocols have recently been developed to produce stem cell-derived α (SC-α) cells as a potential component of a complete cell-based therapy for T1D, to complement the more widely studied stem cell-derived β (SC-β) cells. Differentiation protocols for SC-β cells produce off-target cell populations implicated in the development of outgrowths in SC-β cell grafts, but outgrowths from SC-α cells have not been explored. This study identifies that engrafted SC-α cells generate outgrowths of similar composition to SC-β cell outgrowths. Both cell types share outgrowth-driving populations marked by SOX9, CDX2, or SOX2. Single-cell RNA sequencing was used to reveal an enrichment in cell-adhesion signaling events in outgrowth-driving populations. Small-molecule inhibition of the Notch pathway was insufficient to disrupt all three outgrowth-driving populations. A comprehensive disruption of cell-adhesion signaling via single-cell dispersion and reaggregation is found to reduce the outgrowth propensity in engrafted SC-α and SC-β cells. Together, these results suggest that disrupting residual progenitor cells with SC-α and SC-β cell clusters can enhance the safety profile of these cell therapy products for T1D therapy.

The rates of diabetes throughout the world are rising rapidly, impacting nearly every country. New research is focused on better ways to monitor and treat this disease. Breath acetone levels have been defined as a biomarker for diabetes. The development of a method to monitor and diagnose diabetes utilizing breath acetone levels would provide a fast, easy, and non-invasive treatment option. An ideal material for point-of-care diabetes management would need to have a high response to acetone, high acetone selectivity, low interference from humidity, and be able to operate at room temperature. Chemiresistive gas sensors are a promising method for sensing breath acetone due to their simple fabrication and easy operation. Certain semiconductor materials in chemiresistive sensors can react to acetone in the air and produce changes in resistance that can be correlated with acetone levels. While these materials have been developed and show strong responses to acetone with good selectivity, most of them must operate at high temperatures (compared to RT), causing high power consumption, unstable device operation, and complex device design. In this paper, we systematically studied a series of 2-dimensional MXene-based nanocomposites as the sensing materials in chemiresistive sensors to detect 2.86 ppm of acetone at room temperature. Most of them showed great sensitivity and selectivity for acetone. In particular, the 1D/2D CrWO/Ti3C2 nanocomposite showed the best sensing response to acetone: nine times higher sensitivity than 1D KWO nanowires. To determine the sensing selectivity, a CrWO/Ti3C2 nanocomposite-based sensor was exposed to various common vapors in human breath. The result revealed that it has excellent selectivity for acetone, and far lower responses to other vapors. All these preliminary results indicate that this material is a promising candidate for the creation of a point-of-care diabetes management device.