Diabetes afflicts more than half a billion individuals worldwide, representing a monumental healthcare challenge with complex metabolic ramifications. Central to both autoimmune type 1 diabetes and the stress-related type 2 form is the impairment of pancreatic islets: intricate clusters of cells within the pancreas that orchestrate blood glucose homeostasis. These islets, a form of organoid mini-organs, house insulin-producing beta cells whose dysfunction precipitates the characteristic hyperglycemia of diabetes. Harnessing lab-grown, stem cell–derived islets to replace damaged native islets has emerged as a promising frontier in regenerative medicine, offering potential curative avenues. Yet, a major obstacle has been the inconsistent quality and maturity of these synthetic islets, largely due to the absence of reliable molecular markers that delineate truly functional cells suitable for clinical transplantation.
In a landmark study recently featured in Nature Communications, Dr. Eiji Yoshihara—a leading biomedical investigator associated with The Lundquist Institute at Harbor-UCLA Medical Center and the David Geffen School of Medicine at UCLA—and his multidisciplinary research team have unveiled a pivotal breakthrough in this domain. They identified the gene FXYD2 as a definitive biomarker capable of characterizing both the functional maturity and heterogeneity of stem cell–derived islet organoids. This discovery empowers researchers to clearly segregate high-quality, therapeutically viable islets from their less mature or dysfunctional counterparts, thus establishing a novel paradigm for functional selection that transcends conventional measures such as insulin expression alone.
The significance of FXYD2 extends beyond its utility as a marker; it actively participates in the molecular orchestration of β cell identity and maturation. Unlike previous biomarkers that primarily serve as passive indicators, FXYD2 localizes to the cell membrane and acts as a “kinase signal extender”, forming complexes involved in ion channel-mediated signal transduction. This phenomenon reveals a unique mechanistic insight into mammalian cellular signaling — whereby a membrane-bound protein modulates nuclear gene expression indirectly, extending the scope of intracellular communication pathways fundamental to cell development and function.
Dr. Yoshihara’s current study builds on his earlier pioneering work published in Nature, where his team successfully engineered functional, immune-evasive human islet-like organoids derived from human pluripotent stem cells (hPSCs). Despite demonstrating the initial potential of these engineered islets, translation into clinical settings was hampered by batch-to-batch variability and unpredictable functional heterogeneity. The integration of over 200,000 single-cell RNA sequencing datasets in the present study allowed the team to identify dysregulated gene sets within hPSC-derived insulin-producing cells. Among these, the mineral absorption pathway—regulated notably by FXYD2—stood out as a critical axis in governing functional maturity.
One of the chief challenges addressed by the researchers was the development of robust metrics for assessing functional competence in stem cell–derived islets beyond mere insulin production. Traditional reliance on insulin expression as a proxy for functionality fails to capture the nuanced spectrum of cellular heterogeneity that influences therapeutic outcomes. By disentangling this heterogeneity through the identification of FXYD2 expression levels, the researchers effectively categorized islet organoids into FXYD2-high and FXYD2-low subpopulations. Functional assays revealed a strong positive correlation between FXYD2 expression and insulin secretion dynamics, underscoring the practical value of this marker in pinpointing clinically effective islets.
Therapeutic efficacy was further validated in severe diabetic animal models, where transplantation of FXYD2-high, insulin-positive islets consistently reversed hyperglycemia. Conversely, animals receiving FXYD2-low counterparts exhibited negligible improvements, affirming the marker’s predictive accuracy. This functional validation not only confirms FXYD2’s role as a biomarker but also solidifies it as a functional regulator imperative for β cell maturation and insulin secretory competence.
The identification of FXYD2 as a dual-function molecule—both a marker and regulator of β cell maturity—carries profound implications for regenerative diabetes therapy. It offers a much-needed solution to the critical issue of quality control in cell-based treatment protocols. By enabling precise selection of transplant-ready islets, the findings pave the way for safer, more effective cell therapy approaches, reducing the variability that has historically impeded clinical translation and enhancing the reproducibility of islet organoid production.
Dr. Yoshihara emphasized the importance of this advancement, noting that the field has long struggled with heterogeneity in stem cell–derived islets that complicates therapeutic application. The ability to functionally select islets based on FXYD2 expression marks a new era in islet transplantation, where efficacy can be reliably predicted and controlled. This refinement elevates the prospect of curing diabetes from a theoretical goal to an attainable clinical reality.
Clarissa Tacto, first author of the study and a research assistant in Dr. Yoshihara’s lab, highlighted the clinical relevance of their findings. She pointed out that cells co-expressing insulin and FXYD2 demonstrated superior glucose-regulating efficacy compared to those expressing insulin alone, underscoring the marker’s role in selecting truly potent therapeutic cells. These insights advance our understanding of β cell functionality at a molecular level and inform future bioengineering of islet organoids.
The impact of this research extends beyond diabetes, as it reveals novel principles of ion channel-mediated signaling and gene regulation within differentiated human cells. The concept of a membrane ion channel component such as FXYD2 acting as a kinase signal extender introduces a new dimension to cell biology, potentially applicable in other regenerative and cellular engineering contexts where maturation and functional integration are essential.
The research team comprised experts from multiple institutions including the Lundquist Institute, University of California Irvine, UCLA, and the University of Oklahoma, reflecting the collaborative nature of this biomedical challenge. Their combined expertise allowed a comprehensive approach encompassing genomics, molecular biology, biochemistry, and in vivo functional assays, culminating in this innovative discovery.
Financial support from esteemed institutions such as the National Institutes of Health, Breakthrough T1D, and the Allen Foundation facilitated the scope and depth of the study. This funding underscores the strategic importance placed on translating stem cell biology advances into therapeutic interventions that can ameliorate chronic diseases like diabetes.
Looking ahead, the discovery of FXYD2 as a functional marker ushers in a new era of precision in islet organoid manufacturing and transplantation. By refining the selection criteria with molecular-level granularity, researchers and clinicians can enhance the predictability, safety, and efficacy of cell therapies aimed at restoring endogenous insulin regulation. This breakthrough thus illuminates a promising trajectory toward developing curative treatments for diabetes that have long eluded medical science.
Subject of Research: Stem cell–derived pancreatic islets and diabetes therapy
Article Title: FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction
News Publication Date: 4-Jun-2025
Web References:
References:
Tacto C, Tahbaz M, Salib A, Wang S, Cayabyab F, Choi J, Kim K, Hamba Y, Perez H, Gershon PD, Damoiseaux R, Oh TG, Yoshihara E. FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction. Nature Communications. 2025 Jun 4; DOI:10.1038/s41467-025-60188-4.
Image Credits: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Keywords: Metabolic disorders, Type 1 diabetes, Type 2 diabetes, Insulin
