Background: Processes that activate the immune system during lung transplantation can lead to primary graft dysfunction (PGD) or allograft rejection.Methods: We analyzed cytokine expression profiles after reperfusion and allograft outcomes in a cohort of patients (n = 59) who underwent lung transplantation off‐pump (n = 26), with cardiopulmonary bypass (CPB; n = 18), or with extracorporeal membrane oxygenation (ECMO; n = 15). Peripheral blood was collected from patients at baseline and at 6 and 72 h after reperfusion. To adjust for clinical differences between groups, we utilized a linear mixed model with overlap weighting.Results: PGD3 was present at 48 or 72 h after reperfusion in 7.7% (2/26) of off‐pump cases, 20.0% (3/15) of ECMO cases, and 38.9% (7/18) of CPB cases (p = 0.04). The ECMO and CPB groups had greater reperfusion‐induced increases in MIP‐1B, IL‐6, IL‐8, IL‐9, IL1‐ra, TNF‐alpha, RANTES, eotaxin, IP‐10, and MCP‐1 levels than the off‐pump group. Cytokine expression profiles after reperfusion were not significantly different between ECMO and CPB groups.Conclusion: Our data suggest that, compared with an off‐pump approach, the intraoperative use of ECMO or CPB during lung transplantation is associated with greater reperfusion‐induced cytokine release and graft injury.

Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term ‘stem cell therapy’ is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

Close examination of the initial results of cardiovascular cell therapy clinical trials indicates the importance of patient-specific differences on outcomes and the need to optimize or customize cell therapies. The fields of regenerative medicine and cell therapy have transitioned from using heterogeneous bone marrow mononuclear cells (BMMNCs) to mesenchymal stromal cells (MSCs), which are believed to elicit benefits through paracrine activity. Here, we examined MSCs from the BMMNCs of heart failure patients enrolled in the FOCUS-CCTRN trial. We sought to identify differences in MSCs between patients who improved and those who declined in heart function, regardless of treatment received. Although we did not observe differences in the cell profile of MSCs between groups, we did find significant differences in the MSC secretome profile between patients who improved or declined. We conclude that “mining” the MSC secretome may provide clues to better understand the impact of patient characteristics on outcomes after cell therapy and this knowledge can inform future cell therapy trials.

Background: In ischemic heart failure, the biological mechanisms underlying the benefits of mesenchymal stromal cells (MSCs) and c‐kit–positive cardiac progenitor cells (CPCs) remain incompletely understood. Methods: In this predefined secondary biomarker analysis of 96 patients from the multicenter, randomized, double‐blind, placebo‐controlled Cardiovascular Cell Therapy Research Network CONCERT‐HF (Combination of Mesenchymal and c‐Kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure) trial, plasma biomarkers were measured at baseline and at days 7, 30, and 180. Changes were assessed using 2‐sample randomization median tests and multivariate 2‐sample Cramér–von Mises tests to evaluate time point–specific and trajectory‐level effects. Complementary longitudinal mixed‐effects models were used to assess treatment×time interactions. Results: Cell therapy induced distinct, time‐dependent biomarker changes. Significant reductions were observed in TRAIL‐R1 (tumor necrosis factor receptor superfamily member 10A; MSCs+CPCs), IL‐33 (interleukin‐33), and GDF‐15 (growth differentiation factor 15; MSCs, CPCs), PTX3 (pentraxin 3; MSCs, and MSCs+CPCs), TNF‐α (tumor necrosis factor‐alpha; MSCs and MSCs+CPCs), and PDGF‐BB (platelet‐derived growth factor‐BB; all cell therapy groups). VEGF‐A (vascular endothelial growth factor A), HGF (hepatocyte growth factor), and BMP‐9 (bone morphogenetic protein 9) also decreased significantly in the MSCs cohort. Multivariate 2‐sample Cramér–von Mises test confirmed significant treatment‐related shifts in biomarker trajectories for PTX3, TNF‐α, PDGF‐BB, GDF‐15, BMP‐9, and MMP‐1 (matrix metalloproteinase‐1). Complementary longitudinal mixed‐effects modeling demonstrated significant treatment×time interactions for TNF‐α, MMP‐1, and BMP‐9. Among individual contrasts, PDGF‐BB showed the most consistent treatment effect, including a reduction in the MSCs group versus placebo at day 30 (estimate, −157.98 [95% CI, −286.04 to −29.91]; P =0.01). Time‐specific treatment contrasts for most other biomarkers were modest with wide CIs. Greater increases in PDGF‐BB at day 180 were associated with smaller improvements in Minnesota Living With Heart Failure Questionnaire scores. Conclusions: MSCs, CPCs, and their combination are associated with selective, time‐dependent modulation of inflammatory and matrix remodeling biomarkers in ischemic heart failure. These findings provide mechanistic insight into cell therapy effects and identify PDGF‐BB, PTX3, TNF‐α, MMP‐1, and BMP‐9 as candidate biomarkers for response monitoring and hypothesis generation in future regenerative trials. Registration: URL: https://clinicaltrials.gov ; Unique Identifier: NCT02501811.