Improved efficacy of mesenchymal stromal cells stably expressing CXCR4 and IL-10 in a xenogeneic graft versus host disease mouse model

Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. In vitro experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF-1α and also improved their immunomodulatory properties compared to unmodified Ad-MSCs (WT-MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3+-IL10+ cells), and increased the number of regulatory T and B cells. Our in vitro and in vivo studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.

[1]  J. Pérez-Simón,et al.  Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience , 2022, Stem cells translational medicine.

[2]  J. Lammerding,et al.  Enucleated human mesenchymal stromal cells for the homing and the delivery of therapeutic cargos in vivo , 2021, Nature Biomedical Engineering.

[3]  U. Galderisi,et al.  Clinical Trials Based on Mesenchymal Stromal Cells are Exponentially Increasing: Where are We in Recent Years? , 2021, Stem cell reviews and reports.

[4]  J. Antin,et al.  GVHD Prophylaxis 2020 , 2021, Frontiers in Immunology.

[5]  R. Yañez,et al.  The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy , 2021, Frontiers in Cell and Developmental Biology.

[6]  N. Kröger,et al.  Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years , 2021, Bone Marrow Transplantation.

[7]  R. Yañez,et al.  Enhanced anti-inflammatory effects of mesenchymal stromal cells mediated by the transient ectopic expression of CXCR4 and IL10 , 2021, Stem cell research & therapy.

[8]  A. Erbacher,et al.  Long-term follow-up after the application of mesenchymal stromal cells in children and adolescents with steroid-refractory graft-versus-host disease. , 2021, Stem cells and development.

[9]  G. Hill,et al.  Current Concepts and Advances in Graft-Versus-Host Disease Immunology. , 2021, Annual review of immunology.

[10]  E. Shpall,et al.  A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease. , 2020, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[11]  M. Mohty,et al.  Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. , 2020, The New England journal of medicine.

[12]  J. Laffey,et al.  Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis , 2019, Journal of clinical medicine.

[13]  L. Kanz,et al.  Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation , 2019, Bone Marrow Transplantation.

[14]  Xiangbei Qi,et al.  Treatment of Type II Collagen-Induced Rat Rheumatoid Arthritis Model by Interleukin 10 (IL10)-Mesenchymal Stem Cells (BMSCs) , 2019, Medical science monitor : international medical journal of experimental and clinical research.

[15]  H. Lazarus,et al.  Allogeneic hematopoietic cell transplantation; the current renaissance. , 2019, Blood reviews.

[16]  Haitao Du,et al.  Mesenchymal stem cells and CXC chemokine receptor 4 overexpression improved the therapeutic effect on colitis via mucosa repair , 2018, Experimental and therapeutic medicine.

[17]  L. Dong,et al.  Mesenchymal Stem Cells Inhibited Dendritic Cells Via the Regulation of STAT1 and STAT6 Phosphorylation in Experimental Autoimmune Uveitis. , 2018, Current molecular medicine.

[18]  N. Arsenijević,et al.  Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase‐ and indoleamine 2,3‐dioxygenase‐dependent manner , 2018, Journal of tissue engineering and regenerative medicine.

[19]  Anoop Babu Vasandan,et al.  Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism , 2016, Scientific Reports.

[20]  K. Ozawa,et al.  Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study , 2016, International Journal of Hematology.

[21]  E. Andreu,et al.  Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[22]  H. Li,et al.  Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5+ regulatory B cells producing interleukin 10 , 2014, Leukemia.

[23]  F. Nestle,et al.  Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype , 2012, PloS one.

[24]  G. Pizzolo,et al.  Toll‐Like Receptor‐3‐Activated Human Mesenchymal Stromal Cells Significantly Prolong the Survival and Function of Neutrophils , 2011, Stem Cells.

[25]  Z. Madeja,et al.  Genetically modified adipose tissue-derived mesenchymal stem cells overexpressing CXCR4 display increased motility, invasiveness, and homing to bone marrow of NOD/SCID mice. , 2011, Experimental hematology.

[26]  J. Scheller,et al.  The pro- and anti-inflammatory properties of the cytokine interleukin-6. , 2011, Biochimica et biophysica acta.

[27]  C. Jorgensen,et al.  Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype , 2010, The Journal of Immunology.

[28]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[29]  E. Riley,et al.  IL-10: The Master Regulator of Immunity to Infection , 2008, The Journal of Immunology.

[30]  L. Ou,et al.  Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  C. Min,et al.  IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation , 2007, Bone Marrow Transplantation.

[32]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[34]  M. Jordana,et al.  IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. , 1998, The Journal of clinical investigation.

[35]  M. Scarsella,et al.  Inhibition of B-cell proliferation and antibody production by mesenchymal stromal cells is mediated by T cells. , 2015, Stem cells and development.

[36]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.