EFFICACY AND SAFETY OF ALLOGENEIC MESENCHYMAL STEM CELLS IN THE TREATMENT OF SEPSIS IN INTENSIVE CARE SETTINGS

Abstract

Introduction. Sepsis remains a leading cause of global mortality, accounting for approximately 20% of all deaths worldwide. In Ukraine, mortality rates in anesthesiology and intensive care units (AICUs) remain persistently high (40– 60%), correlating with demographic aging, high levels of comorbidity, and shifts in the epidemiological structure of infections following the COVID-19 pandemic. The limited efficacy of standard protocols necessitates the development of adjuvant therapeutic methods. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are considered a potential therapeutic agent due to their immunomodulatory, antimicrobial, and regenerative properties, which are mediated through paracrine mechanisms influencing the systemic inflammatory response. Objective. To evaluate the efficacy and safety of allogeneic umbilical cord mesenchymal stem cells (UC-MSCs) as an adjuvant therapy for the treatment of sepsis in intensive care unit patients, focusing on immunomodulation, organoprotection, and mortality reduction. Materials and Methods. A comprehensive review of publications and databases was conducted, including PubMed, Web of Science, Scopus, and clinical registries (ClinicalTrials.gov) regarding sepsis and septic shock where mesenchymal stem cells, specifically UC-MSCs, were utilized in treatment protocols. The analysis encompassed preclinical models using MSCs/UC-MSCs, Phase I–II clinical trials in humans with sepsis, as well as systematic reviews and meta-analyses assessing mortality, organ dysfunction, and biomarkers. Results. Systematization of preclinical data (CLP models) demonstrated a reduction in mortality with UC-MSC application (OR 0.26) and improvement in functional indicators of the kidneys (creatinine ROM 0.63) and liver (ALT ROM 0.69). The pathophysiological effect is based on the secretion of paracrine factors (TSG-6, PGE2, IDO), which initiate macrophage polarization into an anti-inflammatory M2 phenotype and reduce levels of pro-inflammatory cytokines (TNF-α decreased by 30–60%, IL-6 – ROM 0.67). Direct antimicrobial activity (via the LL-37 peptide) and potentiation of pathogen phagocytosis were established. Phase I clinical trial results confirmed the safety of intravenous infusions at doses up to 3х106 cells/kg. A statistically significant reduction in C-reactive protein levels (~40% by day 8) and a positive trend in procalcitonin were observed, indicating a limitation of the systemic inflammatory response. Conclusions. Allogeneic umbilical cord MSCs represent a pathogenetically justified and promising adjuvant therapy for sepsis, though currently validated primarily at the level of preclinical models and early-phase clinical trials. Their primary mechanism of action is paracrine immunomodulation: suppression of pro-inflammatory cytokines, enhancement of the anti-inflammatory response, increased phagocytosis, and organoprotection, accompanied by reduced mortality and severity of organ dysfunction in experimental settings. Phase I human trials confirmed the safety of intravenous UC-MSC administration and favorable cytokine/ CRP dynamics; however, as conclusive data on mortality reduction are still lacking, their application should remain within the framework of clinical trials.