Adjunct cell therapy for hypoplastic left heart syndrome: therapeutic promise requires targeted design strategy

Letter to the editor regarding: Gallego-Navarro C, Jaggers J, Burkhart HM, Carlo WF, Morales DL, Qureshi MY, Rossano JW, Hagen CE, Seisler DK, Peral SC, Nelson TJ. Autologous umbilical cord blood mononuclear cell therapy for hypoplastic left heart syndrome: a nonrandomized control trial of the efficacy and safety of intramyocardial injections. Stem Cell Res Ther. 2025 May 1;16(1):215. doi: https://doi.org/10.1186/s13287-025-04316-3 . This phase IIb clinical cell therapy trial with autologous cord blood mononuclear cells is notable and highly commended as an important effort in very challenging clinical conditions in which new cell treatment advancements have been limited. In light of their findings of unfavourable clinical findings, our letter highlights that their study is intertwined with the complexity of the clinical pathology within immature pediatric hearts, cardiac surgical intervention strategy and other related study design hurdles. These difficulties contribute to confound the interpretation of cell treatment efficacy and clinical safety. Based on this study and our own recent clinical study, we make a call for future studies testing cell therapy in the congenital heart disease setting, to implement far greater consideration of the mode and timing of cell delivery and congruency with myocardial tissue remodelling and developmental growth processes in small hearts.