The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease

Abstract

Background/Aims: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM-1^highMSCs may significantly improve their immunomodulatory effect. Methods: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1^highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. Results: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1^highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1^highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. Conclusions: Taken together, these data demonstrate that ICAM-1^highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD.

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

“…For example, we detected intercellular adhesion molecule-1 (ICAM-1), which promotes leukocyte accumulation into the wound site required for wound healing [40]. ICAM-1 also has immunosuppressive effects on dendritic cells and T cells, which may aid in the treatment of graft versus host diseases [41]. We detected expression of monocyte chemotactic protein-1 (aka CCL2), a pro-inflammatory cytokine, which promotes wound healing, including in hard to heal diabetic wounds [42].…”

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

“…To date, according to the ClinicalTrials.gov website of NIH, a total number of 983 clinical studies have been registered for series of disease treatment, such as hematological malignancies, acute-on-chronic liver failure, acute severe respiratory failure, type I and II diabetes, psoriasis, graft-versus-host disease (GVHD), cerebral palsy, ulcerative colitis, and even wound healing [11][12][13][14][15]. Meanwhile, several preclinical studies on disease treatment are in process as well, including acute myocardial infarction (AMI), rheumatoid arthritis (RA), osteoarthritis, critical limb ischemia (CLI), and aplastic anemia [5,[16][17][18][19]. Of these studies, we and other investigators have indicated the efficacy of human umbilical cord mesenchymal stem cells (hUC-MSCs), which are promising sources without limitation in supply [15,20,21].…”

GVHD-derived plasma as a priming strategy of mesenchymal stem cells

“…Interestingly, though, this effect was gradually increased as MSCs were primed with higher concentrations of cGVHD plasma. Recently, Tang and colleagues demonstrated that MSCs overexpressing ICAM-1 prolonged the survival of mice with GVHD [39]. In accordance with such observation, MSCs overexpressing ICAM-1 were shown to possess stronger therapeutic effects than ICAM-1-low MSCs in a mouse model of inflammatory bowel disease [40].…”