The review, led by Yuyao Lin and Yujie Yan of the First Affiliated Hospital of Xi’an Jiaotong University, synthesizes preclinical evidence across three major therapeutic platforms: iPSC-derived cells, iPSC-derived extracellular vesicles, and three-dimensional tissue-engineered skin substitutes. The authors argue that iPSCs hold several decisive advantages over both embryonic stem cells and adult stem cells currently under investigation. Because iPSCs are generated by reprogramming a patient’s own easily obtained cells, such as skin fibroblasts or blood cells, they sidestep the ethical controversies surrounding embryo-derived material and eliminate the need for invasive harvesting procedures like bone marrow aspiration or fat biopsies. Once reprogrammed using the now-famous quartet of transcription factors identified by Shinya Yamanaka, OCT-3/4, SOX2, c-MYC, and KLF4, iPSCs regain the pluripotency of embryonic cells, meaning they can in principle become every cell type found in healthy skin.

That versatility is precisely what chronic wounds need. Normal healing unfolds through four overlapping phases: coagulation, inflammation, migration and proliferation, and remodeling. Chronic wounds stall somewhere in this choreography, exhibiting impaired growth factor production, reduced angiogenesis, elevated inflammatory markers, and poor cellular proliferation. In diabetes, persistent hyperglycemia disrupts inflammation, angiogenesis, vascular permeability, and endothelial progenitor cell function all at once. The review details how iPSC-derived mesenchymal stem cells, endothelial cells, vascular smooth muscle cells, fibroblasts, epithelial stem cells, and keratinocytes each target a different failure point. In wounded immunodeficient mice, for example, iPSC-derived mesenchymal cells established even from a patient with recessive dystrophic epidermolysis bullosa produced detectable human type VII collagen at the dermal-epidermal junction of healed tissue, demonstrating biological activity relevant to skin repair.

The vascular story is particularly compelling. Angiogenesis, the growth of new blood vessels from pre-existing ones, is essential for restoring oxygen and nutrient delivery to injured tissue, and it is markedly impaired in chronic and diabetic wounds. The review describes how iPSC-derived endothelial cells applied topically to excisional wounds accelerated closure and perfusion-linked outcomes in preclinical models. Even more striking, co-implantation of iPSC-derived endothelial cells with iPSC-derived vascular smooth muscle cells produced enhanced angiogenesis, greater arteriole density, and faster wound healing than endothelial cells alone. Vascular smooth muscle cells embedded in collagen scaffolds secrete a cocktail of pro-repair mediators, including VEGF-A, basic fibroblast growth factor, and IL-10, collectively supporting vessel formation while tempering inflammation in both acute and diabetic wound models.

Perhaps the most strategically important finding is that many of these benefits do not require the transplanted cells to survive at all. Longitudinal tracking using firefly luciferase reporter genes revealed that iPSC-derived endothelial cells showed a substantial and progressive decline in survival over time, yet the therapeutic benefits persisted. The explanation lies in paracrine signaling: cells secrete extracellular vesicles, tiny membrane-bound packages loaded with proteins, lipids, and regulatory RNAs, that reprogram the behavior of recipient cells in the wound bed. This insight has spawned a cell-free therapeutic paradigm. Extracellular vesicles harvested from iPSC-derived cells offer advantages in manufacturing, storage, and delivery, and because they are acellular and non-replicative, they are not expected to form teratomas, the tumors that can arise from residual undifferentiated pluripotent cells.

The mechanistic detail emerging from this work is remarkable. Recent studies show that exosomes from iPSC-derived mesenchymal stem cells promote wound healing by delivering FGF2 to the FGFR3 receptor on keratinocytes, activating the p38 pathway to enhance proliferation and migration while dampening inflammation. Another team demonstrated that microvesicles from iPSCs accelerate deep second-degree burn healing through a specific microRNA cargo, miR-16-5p, that boosts keratinocyte migration. In diabetic mouse models, iPSC-derived extracellular vesicles coupled pro-vascularization signals with strong anti-inflammatory activity, shifting macrophage states toward repair and inhibiting T-cell proliferation. Meanwhile, engineered skin substitutes built entirely from iPSC-derived keratinocytes and fibroblasts have achieved increasingly human-like architecture, and a landmark study generated hair-bearing skin from pluripotent stem cells that integrated seamlessly with host tissue without ulcers or tumors.

Yet the review is notably candid about the obstacles standing between bench and bedside. The most serious is tumorigenicity. Even a minuscule residual fraction of undifferentiated cells, on the order of 0.01 percent, can give rise to teratomas, and standard flow cytometry typically detects rogue pluripotent cells only at frequencies around 0.1 percent. Reprogramming itself can inflict genomic damage, and reactivation of the c-MYC oncogene has produced somatic tumors in animal models. Safer non-integrative approaches, including Sendai virus vectors, episomal plasmids, and even purely chemical reprogramming using small molecules, are advancing rapidly, but the authors stress that no current quality control method can guarantee complete elimination of pluripotent contaminants.

Immunocompatibility presents a second frontier. Autologous iPSC therapies avoid rejection but are slow, expensive, and potentially compromised by the patient’s own disease: cells from diabetic patients carry epigenetic memory and metabolic dysfunction that can persist after reprogramming, and iPSC-derived endothelial cells from obese diabetic mice show impaired function compared with healthy controls. Allogeneic, off-the-shelf products from healthy young donors promise scalability and standardized manufacturing, but require immune engineering. Researchers have used CRISPR-Cas9 to create hypoimmunogenic universal iPSC lines by disrupting HLA class I and II expression while preserving HLA-E or HLA-C, or by overexpressing the CD47 don’t-eat-me signal. One such strategy of twelve HLA-C-retained lines could theoretically match more than ninety percent of the world’s population. The catch is that dampening immune recognition may also blunt immune surveillance against emerging tumors, prompting calls for built-in suicide switches such as ganciclovir-sensitive thymidine kinase genes.

Practical and economic hurdles loom as well. Manufacturing clinical-grade iPSC products is estimated to cost between five thousand and fifty thousand dollars per line, before accounting for GMP facility infrastructure and rigorous quality release testing. Tissue-engineered skin substitutes still lack functional vasculature, nerves, sweat glands, and immune cells, and without rapid vascular inosculation, grafts cannot survive beyond a certain thickness. The review also emphasizes that most evidence comes from small rodent models with short follow-up, heterogeneous dosing, and inconsistent endpoints, and that no head-to-head trials have yet demonstrated clear superiority of iPSC-derived products over adult stem cells or advanced dressings. Still, the authors conclude that iPSCs should be viewed not as a universal cure but as an adaptable regenerative platform whose value depends on implementation. With standardized potency assays, clinically relevant large-animal models, and rigorous long-term safety assessment under GMP-compatible workflows, reprogrammed cells and their vesicles could ultimately transform care for millions of patients whose wounds simply refuse to heal.

Subject of Research: Induced pluripotent stem cell-based therapies for chronic wound healing

Article Title: Application and progress of induced pluripotent stem cells in chronic wound healing: a narrative review

Article References: Application and progress of induced pluripotent stem cells in chronic wound healing: a narrative review. (n.d.). https://doi.org/10.1186/s44452-026-00016-w

Image Credits: AI Generated

DOI: 10.1186/s44452-026-00016-w

Keywords: induced pluripotent stem cells, chronic wounds, wound healing, extracellular vesicles, tissue-engineered skin substitutes, diabetic foot ulcers, angiogenesis, regenerative medicine, tumorigenicity, immunocompatibility, cell therapy, mesenchymal stem cells

The concerns identified by the journal center on image integrity problems in key experimental figures, the kind of evidence that readers rely on to judge whether a claim about cancer biology is supported by the data. According to the retraction notice, two pairs of blots in Figure 2A appear to overlap when flipped horizontally: the MEDIUM Vector and SULF2 pair, and the CELL Vector and SULF2 pair. In practical terms, this means that lanes presented as representing different experimental conditions may show substantially the same underlying image, which undermines the comparison the figure was intended to demonstrate. Western blots of this type are a standard molecular biology tool used to detect and compare protein levels, and duplicated or manipulated blots strike at the heart of the quantitative conclusions drawn from them.

Figure 4C raised a similar concern. The notice states that the CTRL NEG and SULF2 panels of DU-145, a human prostate cancer cell line used in the study, appear to overlap. DU-145 cells are a widely used model in prostate cancer research, and figures built on this line were central to the paper’s argument that SULF2 overexpression enhances tumorigenic behavior. When two panels that should show distinct experimental results instead appear to share the same image content, reviewers and editors cannot verify that the reported differences between conditions actually exist. A third issue concerned Figure 1A, where the Publisher noted discrepancies between the original data and the published image, adding to the pattern of concerns about the article’s figure-level evidence.

The retraction process followed the conventions of research integrity oversight. Concerns were raised with the journal, and the Publisher requested source data from the authors, the raw files and records that should allow reviewers to reconstruct how each published figure was produced. According to the notice, the authors provided some source data on request, but this proved insufficient to address the concerns raised. In such cases, an editor must weigh whether the published claims remain trustworthy when their evidentiary basis cannot be confirmed. Here, the Editor-in-Chief concluded that confidence in the reliability of the reported data could no longer be maintained, and the retraction was issued, more than a decade after the original paper first appeared on 14 March 2015.

The response of the authors to the retraction was not uniform, and the notice documents this divergence explicitly. Authors Carolina M. Vicente and Leny Toma disagree with the retraction, a position they are entitled to record in the public notice. Authors Marcelo A. Lima and Helena B. Nader did not respond to any correspondence regarding the retraction. Disagreement among authors is not unusual in retraction cases, and journals typically proceed when the editorial judgment is that the integrity concerns themselves are decisive, regardless of whether all authors accept the outcome. The notice itself does not make findings about intent; it records the figure-level concerns, the insufficiency of the supplied source data, and the resulting loss of confidence in the paper’s reliability.

To understand why the retraction matters scientifically, it helps to consider what SULF2 actually does. SULF2 is an extracellular sulfatase, an enzyme that removes sulfate groups from heparan sulfate chains, the sugar structures that decorate proteins on the cell surface. This desulfation activity can reshape the binding landscape around a cell, influencing how growth factors, signaling molecules and structural components of the extracellular matrix interact with the cell. Because heparan sulfate mediates many signals that govern cell growth, migration and organization, enzymes like SULF2 have attracted sustained interest in cancer biology as potential regulators of tumor behavior. The retracted 2015 paper had argued for a specific, positive role for SULF2 in driving the tumorigenicity of prostate cancer cells, a claim that intersected with broader debates about whether the enzyme acts to promote or suppress tumor progression in different contexts.

Prostate cancer research depends heavily on cell line models such as the DU-145 cells used in the study, and on protein-level comparisons like those presented in the affected figures. Experimental conclusions in this field feed into larger narratives about molecular markers that might distinguish aggressive disease from indolent disease, and about enzymes and signaling pathways that could serve as therapeutic targets. When a paper claiming a regulatory role for an enzyme like SULF2 is retracted, the finding itself is removed from the citable literature, and researchers weighing the enzyme’s role must rely on the remaining evidence base. Retraction notices thus function as a correction mechanism for the scientific record, ensuring that claims no longer supported by verifiable data are clearly flagged rather than silently persisting in citation networks.

The case also illustrates the technical mechanics of modern image integrity screening. Overlapping blots, such as those described for Figure 2A, can often be detected by digital analysis that reveals when two image regions are identical or mirrored copies of one another, even after adjustments to brightness or contrast. Horizontal flipping is a common manipulation because it can make duplication harder to spot by eye, but pixel-level comparison reliably exposes it. The detection of such overlaps does not by itself explain how they arose, which is why journals request original source data from authors. When that data is incomplete or does not resolve the discrepancies, as occurred here, the standard editorial response is retraction, because the scientific record must be able to distinguish between results that can be verified and those that cannot.

The retracted article remains publicly accessible under the journal’s open access framework, as does the retraction notice itself, published under a Creative Commons Attribution 4.0 International License. The notice identifies the original publication as J Exp Clin Cancer Res 34, 25 (2015), and the retraction record as volume 45, article number 203 (2026), carrying the DOI 10.1186/s13046-026-026-03833-0 in the journal’s records. The eleven-year gap between publication and retraction reflects the reality that integrity concerns can surface long after a paper first appears, prompted by reader scrutiny, improved detection tools, or editorial reviews. For the prostate cancer research community, the retraction’s practical effect is clear: the specific claim that SULF2 overexpression positively regulates the tumorigenicity of human prostate cancer cells, as reported in that paper, should no longer be treated as established findings, and future work on SULF2 must rest on independently verified evidence.

Beyond the individual paper, the case is a reminder of the infrastructure that keeps biomedical literature trustworthy. Editors, publishers and integrity reviewers act as a system of verification that operates after publication, using source data requests, image forensics and author correspondence to resolve doubts. The outcome here, a retraction with documented author disagreement and partial non-response, follows established norms: the journal published the specific figure-level concerns, described the insufficiency of the supplied data, and recorded each author’s stance. Readers encountering SULF2-related findings in prostate cancer or in heparan sulfate biology generally should note this retraction when tracing the enzyme’s regulatory role back through the literature, since one of the papers that once supported a tumor-promoting role in prostate cancer cells is now formally withdrawn from the scientific record.

Subject of Research: Retraction of a study on SULF2 overexpression and tumorigenicity in human prostate cancer cells

Article Title: Retraction Note: SULF2 overexpression positively regulates tumorigenicity of human prostate cancer cells

Article References: Vicente, C. M., Lima, M. A., Nader, H. B., & Toma, L. (2026). Retraction Note: SULF2 overexpression positively regulates tumorigenicity of human prostate cancer cells. Journal of Experimental & Clinical Cancer Research, 45(1), Article 203. https://doi.org/10.1186/s13046-026-03833-0

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03833-0

Keywords: SULF2, prostate cancer, retraction, research integrity, DU-145, Western blot, image duplication, heparan sulfate, sulfatase, tumorigenicity, Journal of Experimental & Clinical Cancer Research, open access