Illuminating the future of diabetes treatment: Autologous CiPSC-derived islets take center stage

Abstract

The recent clinical success of chemically induced pluripotent stem cell (CiPSC)–derived islet transplantation for type 1 diabetes represents a landmark achievement in regenerative medicine. This article delves into the groundbreaking work presented by Dr. Hongkui Deng and Dr. Candice S.Y. Liew at International Society for Stem Cell Research (ISSCR) 2025, focusing on their innovative chemical reprogramming technology and its clinical application. The discussion highlights the scientific rationale behind chemical reprogramming, the development of functional islets, the novel transplantation strategy, and the remarkable clinical outcomes observed in their first patient. The implications for future stem cell therapies and the challenges of scalability are also explored.

The field of stem cell research has witnessed remarkable progress since the discovery of induced pluripotent stem cells (iPSCs) by Yamanaka nearly 20 years ago. ¹ While traditional genetic reprogramming methods have proven valuable, they carry limitations including genomic integration risks and variability in efficiency. Dr. Hongkui Deng’s pioneering work on chemical reprogramming offers an alternative approach that addresses these challenges while opening new possibilities for clinical translation.^2–4

The three pillars of cell therapy

At the heart of Dr. Hongkui Deng’s vision lies a critical framework for cell therapy: “There are three different levels: xenograft, allograft, and autologous cells.” This tripartite strategy defines the future of cell therapy, organ or tissue transplantation, with autologous approaches emerging as the most promising path to overcoming immune barriers. As Dr. Deng emphasized, while both xenografts (cross-species transplants) and allografts (transplants between genetically non-identical humans) face significant immunological barriers, autologous therapies, using a patient’s own cells, can circumvent rejection risks by avoiding HLA incompatibility, thereby potentially obviating the need for lifelong immunosuppression.

Chemical reprogramming: a novel pathway to pluripotency

Dr. Deng’s journey into chemical reprogramming began with his longstanding interest in chemical biology. “When I finished my PhD at UCLA in 1995, chemical biology was a new concept,” he recalled. This interest culminated in his development of chemically induced pluripotent stem cells (CiPSCs), which was achieved through a fundamentally different mechanism than Yamanaka’s genetic approach and could directly address the immune-hierarchical issues above. Unlike genetic reprogramming (which relies on viral vectors and risks genomic instability), chemical reprogramming uses small-molecule cocktails to reset somatic cells to pluripotency. This method avoids foreign DNA integration, creating cells ideal for autologous therapies.

The chemical reprogramming strategy emerged from several key insights. First, Dr. Deng noted that “if you look at lower animal model species that are highly regenerative, they’re not using Yamanaka factors.” These organisms achieve regeneration through responses to extrinsic stimuli, suggesting that chemical approaches could mimic natural processes more closely than genetic manipulation.

The development process was methodical. “At the beginning, we used three Yamanaka factors, then found small molecules to replace them,” Dr. Deng explained. Through systematic screening, his team identified a cocktail of chemicals that could initiate somatic cell differentiation without relying on exogenous transcription factors.

His team’s breakthrough, published earlier this year, achieves CiPSC generation in just 10 days with near-100% efficiency—even from 91-year-old donors. This scalability is foundational for democratizing autologous treatments. As Dr. Deng noted, “The advantage of chemical reprogramming? You don’t need special equipment. Just change the media. It’s standardized, simple, and accessible—like buying reagents from StemCell Technologies.”

From CiPSCs to functional islets

The translation of CiPSCs into clinically relevant cell types fell to Dr. Candice S.Y. Liew, who got trained in Dr. Deng’s lab. “We do directed differentiation, mimicking the embryonic developmental process of islets in the body,” she described. The protocol progressed through stages: from pluripotent stem cells to pancreatic progenitors, then to endocrine progenitors, and finally to mature islet cells.

A critical challenge was optimizing the later differentiation stages. “At stage four to five, cells face a critical fate choice,” Dr. Liew noted. The team focused on ensuring robust production of beta cells, the insulin-producing cells essential for diabetes treatment. Their efforts resulted in islets that demonstrated therapeutic efficacy in animal models, including nonhuman primates.

Innovative transplantation strategy

A key breakthrough came with the development of a novel transplantation site. Initial attempts using the hepatic portal vein, the standard site for islet transplants, showed limited success. “We lost 40-80% of cells in one week with the liver portal approach,” Dr. Deng observed. Drawing from their experience with kidney capsule transplants in mice, the team identified the anterior abdominal rectus sheath as an alternative site that provided better cell survival and vascularization.

“This new site is more like a kidney capsule—it’s easier for cells to get vascularized and survive,” Dr. Deng explained. This innovation proved crucial, as only with this approach did they achieve curative insulin secretion levels in their primate studies.

Clinical translation and outcomes

The first human trial involved a patient with a history of liver transplantation, allowing the team to leverage existing immunosuppressive therapy. The results were striking. “After 75 days post-transplantation, the patient became completely insulin independent,” Dr. Deng reported. The patient, who had not eaten ice cream for 11 years due to diabetes restrictions, could now enjoy sugar-containing foods freely.

Dr. Liew emphasized the robustness of their protocol: “We see insulin secretion levels return to normal, with HbA1c recovering to about 5%.” The speed did match what they saw in preclinical studies, but it was surprising how well the process translated in their first-in-human study.

Future directions and challenges

Looking ahead, Dr. Deng highlighted several priorities. First is improving the efficiency of CiPSC generation: “This year we published a new protocol that takes just 10 days with near-100% success, even with cells from a 91-year-old donor.” Second is expanding applications beyond type 1 diabetes to include insulin-requiring type 2 diabetes patients.

Scalability remains a significant challenge. Dr. Liew described their efforts to transition from “artisanal” lab protocols to standardized bioprocessing. “We’re working on using bioreactors to make the production scalable while maintaining quality,” she said. The chemical reprogramming platform offers advantages here, as Dr. Deng noted: “You don’t need any special equipment—just change the media.”

Conclusion

The work of Dr. Deng and Dr. Liew represents a major advance in regenerative medicine. Their chemical reprogramming technology provides a safer alternative to genetic methods, while their innovative differentiation and transplantation strategies have demonstrated remarkable clinical potential. As Dr. Deng reflected, “The first wave of stem cell therapies has come; the second wave is coming.” Their success with CiPSC-derived islets suggests this second wave may indeed deliver on the long-promised potential of stem cell medicine.

The implications extend beyond diabetes treatment. The principles established—chemical reprogramming, precise differentiation, and innovative delivery—provide a template for addressing other degenerative diseases. As the field progresses, the balance between autologous and allogeneic approaches, the refinement of immune modulation strategies, and the development of scalable manufacturing processes will be critical areas for continued innovation.