Critical Evaluation of Thrombomodulin-Overexpressing Mesenchymal Stem Cells for Renal Ischemia-Reperfusion Injury

We commend Tanaka et al.1 for their innovative study published in JASN on thrombomodulin-overexpressing adipose-derived mesenchymal stem cells (TM-ASCs) as a potential therapy for renal ischemia-reperfusion injury. Their findings suggest that TM-ASCs can mitigate thrombogenic risks and enhance therapeutic outcomes in animal models, offering a promising approach to address the limitations of mesenchymal stem cell therapy. However, several methodological and translational considerations warrant further discussion to strengthen the study's effect and facilitate clinical translation. The study's sample sizes, while sufficient for proof of concept, may limit the generalizability of the findings. With only 11–12 animals per group, particularly in the pulmonary embolism model where mortality differences (0/12 versus 3/12) may not have reached statistical significance, the evidence for universal thrombogenic risk reduction across administration routes is not fully robust. Reporting detailed statistical analyses, such as power calculations or confidence intervals, would enhance confidence in these results and guide future study designs.2 The reliance on adeno-associated virus for thrombomodulin overexpression poses significant challenges for clinical application. Although adeno-associated virus is generally considered safe, potential immunogenicity and uncertainty regarding the duration of thrombomodulin expression remain concerns.3 Alternative strategies, such as nonviral gene delivery methods (e.g., electroporation or lipid nanoparticles) or pharmacological agents like inhibitory kappa-B kinase-β (IKKβ) inhibitors, could offer more clinically viable options. However, the use of IKKβ inhibitors requires careful evaluation of off-target effects because IKKβ is involved in multiple signaling pathways beyond thrombomodulin regulation.4 In addition, the study's exclusive use of young male Sprague-Dawley rats may not fully represent the typical renal ischemia-reperfusion injury patient population, who are often older and have comorbidities such as hypertension or diabetes. Studies in more clinically relevant models, such as aged animals or those with induced pathological conditions, would provide critical insights into TM-ASCs' efficacy and safety.5 While the authors convincingly link TM-ASCs' therapeutic benefits to increased PGE2 secretion and M2 macrophage polarization, other mechanisms may also contribute. A comprehensive analysis of the cellular secretome or transcriptome could uncover additional therapeutic pathways or potential adverse effects. Moreover, the anticoagulant properties of thrombomodulin, while beneficial for reducing thrombosis, may increase bleeding risks, particularly in patients on anticoagulant therapy. This potential risk warrants thorough investigation to ensure clinical safety. To advance TM-ASCs toward clinical application, we propose three improvements: (1) conduct larger, adequately powered animal studies to confirm key findings, particularly for mortality outcomes; (2) explore safer and more translatable methods for enhancing thrombomodulin expression, such as nonviral gene delivery or specific pharmacological agents; and (3) test TM-ASCs in animal models that better reflect the human patient population, including aged animals or those with comorbidities. These steps will be crucial in translating this promising therapy from the laboratory to the clinic.