Pretreatment of Conditioned Medium from Inflammatory Macrophages Amplifies Umbilical Cord Mesenchymal Stem Cell Efficacy and DiminishesMacrophage Crosstalk in Colitis

INTRODUCTION: The hostile inflammatory microenvironment at the injury site often limits the therapeutic potential of human Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) in colitis. To address this challenge, we explored whether priming UC-MSCs with conditioned medium from M1 macrophages (M1-CM) could attenuate detrimental macrophage crosstalk and amplify their immunomodulatory efficacy, improving overall treatment outcomes. METHODS: The M1 macrophage phenotype was induced with LPS and IFN-γ, and M1-CM was collected. UC-MSCs were preconditioned with M1-CM to generate M1UC-MSCs. To assess the therapeutic potential of M1UC-MSCs, a dextran sulfate sodium (DSS)-induced colitis model was established in ICR mice. RESULTS: Preconditioning with M1-CM significantly enhanced the anti-inflammatory properties of UC-MSCs without compromising viability. In vivo, M1UC-MSCs exhibited improved survival and more effectively ameliorated colitis symptoms, reducing disease severity and inflammatory damage compared to non-primed cells. DISCUSSION: These results indicate that inflammatory preconditioning augments the therapeutic function of UC-MSCs by enhancing their adaptability and reducing deleterious interplay with macrophages. This approach is consistent with current strategies to improve cellular tolerance and microenvironmental compatibility. Study limitations include the need for further mechanistic investigation, and subsequent research should prioritize elucidating the specific molecular pathways modulating macrophage-MSC crosstalk. CONCLUSION: M1-CM preconditioning represents a novel and potent strategy to enhance UC-MSCbased therapy for colitis, primarily by improving cellular adaptation and harmonizing the immune response under inflammatory conditions. This method holds significant promise for advancing regenerative medicine applications in colitis.