The International Society for Stem Cell Research (ISSCR) today announced the 10 most downloaded papers of 2025 from Stem Cell Reports, its peer-reviewed, open-access journal. Together, these highly read articles reflect the extraordinary scientific range of the field – from foundational mechanisms of pluripotency and differentiation to translational advances in regenerative medicine, disease modeling, and bioethics – and underscore the journal’s role as a trusted platform for impactful stem cell science.

1. Engineered Proxies and the Illusion of De-Extinction
   A timely and widely discussed perspective examining recent claims of “de-extinction,” using dire wolf-like canids as a case study to question whether phenotypic approximation truly constitutes species restoration – and what such efforts mean scientifically and ethically.
2. Gene Reactivation upon Erosion of X-Chromosome Inactivation in Female hiPSCs
   A mechanistic study revealing that erosion of X-chromosome inactivation in female human iPSCs is frequent, predictable yet variable, and persists through differentiation—raising important considerations for disease modeling and clinical applications.
3. Promoting the Adoption of Best Practices and Standards to Enhance Quality and Reproducibility of Stem Cell Research
   A community-focused call to action outlining strategies to improve rigor, reproducibility, and reporting standards, accelerating the responsible adoption of stem cell-based models in industrial and regulatory settings.
4. Thymosin Beta 4 as an Alzheimer’s Disease Intervention Target Identified Using Human Brain Organoids
   Using patient-relevant brain organoids, this study identifies thymosin beta 4 as a neuroprotective factor capable of rescuing neurodevelopmental deficits and reducing amyloid pathology, pointing to a potential therapeutic avenue for Alzheimer’s disease.
5. Stem Cell-Based Embryo Models: The 2021 ISSCR Stem Cell Guidelines Revisited
   An influential policy and ethics paper reassessing ISSCR guidance on stem cell-based embryo models in light of rapid technological advances, offering updated recommendations to ensure scientific clarity, oversight, and public trust.
6. The Lung Microvasculature Promotes Alveolar Type 2 Cell Differentiation via Secreted SPARCL1
   This developmental biology study identifies SPARCL1 as a key endothelial-derived factor that promotes alveolar maturation through NF-κB signaling, with implications for lung regeneration and repair.
7. Modeling In Vivo Induction of Gastric Insulin-Secreting Cells Using Transplanted Human Stomach Organoids
   Demonstrating the power of organoid-based approaches, this work shows that insulin-secreting cells can be induced from human gastric tissues in vivo, improving glycemic control in experimental diabetes models.
8. Human Cone Photoreceptor Transplantation Restores Function in End-Stage Leber Congenital Amaurosis
   A striking example of regenerative potential, this study shows that transplanted human cone photoreceptors can remodel severely degenerated retinal circuits and restore visually relevant function in a rigorous disease model.
9. Efficient Differentiation of Human iPSCs into Leydig-Like Cells with Long-Term Testosterone Secretion
   Introducing a highly efficient differentiation protocol, this paper advances the feasibility of stem cell–based therapies for late-onset hypogonadism by generating durable, testosterone-producing Leydig-like cells.
10. Transplantation of Genome-Edited Retinal Organoids Restores Fundamental Physiological Functions
    Using genome-edited retinal organoids, this study provides detailed electrophysiological evidence that transplanted tissues can restore light sensitivity and adaptive responses in end-stage retinal degeneration.

These top-downloaded papers exemplify Stem Cell Reports’ mission to publish science that is rigorous, transparent, and consequential – advancing discovery while informing clinical translation, policy, and public understanding.

To explore more articles, visit Stem Cell Reports.

About Stem Cell Reports
Stem Cell Reports is the open access, peer-reviewed journal of the International Society for Stem Cell Research (ISSCR) for communicating basic discoveries in stem cell research, in addition to translational and clinical studies. Stem Cell Reports focuses on original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians. Stem Cell Reports is a Cell Press partner journal. Find the journal on X: @StemCellReports.

About ISSCR
With nearly 5,000 members from more than 80 countries, the International Society for Stem Cell Research (@ISSCR) is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. The ISSCR mission is to promote excellence in stem cell science and applications to human health.