Therapeutic Effects of Genetically Modified Wharton’s Jelly Mesenchymal Stem Cells Expressing Erythropoietin on Cancer-related Anemia in Mice Model

Abstract

BackgroundCancer-related anemia (CRA) negatively influences cancer patients’ survival, disease progression, treatment efficacy, and quality of life (QOL). Current treatments such as iron therapy, red cell transfusion, and erythropoietin-stimulating agents (ESAs) may cause severe adverse effects. Therefore, development of long-lasting and curative therapies is highly required. Combined cell and gene therapy platform can introduce a new route for permanent production of erythropoietin (EPO) in the body with various degrees of clinical benefits and avoiding the need for repeat treatments.MethodsIn this study, we developed cell and gene therapy strategy for in-vivo delivery of EPO cDNA via genetic engineering human Wharton’s jelly mesenchymal stem cells (hWJMSCs) to long-term produce and secret human EPO protein after transplantation into the mice model of CRA. To evaluate CRA's treatment in cancer-free and cancerous conditions, at first, we designed recombinant breast cancer cell line 4T1 expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) by a lentiviral vector encoding HSV1-TK and injected into mice. After 3 weeks, all mice develop the metastatic breast cancer associated to the acute anemia. Then, we administrated ganciclovir (GCV) for 10 days in half of the mice to clear cancer cells. Meanwhile, we designed another lentiviral vector encoding EPO to transduce hWJMSCs. Following implantation of rhWJMSCs-EPO, the whole peripheral blood samples were collected from the tail vein once per week which were immediately analyzed for the measurements of EPO, hemoglobin (Hb), and hematocrit (Hct) plasma levels. Results We found that after implantation of rhWJMSCs-EPO, plasma EPO, Hb, and Hct concentration significantly increased which rose to a peak in the fourth week and remained at a therapeutic level for >17 weeks in the cancer-free group and >10 weeks in the cancerous group.ConclusionOur data indicate that the EPO-transduced hWJMSCs could improve the anemia of cancer in both cancer-free and cancerous mice model. This significant difference in length of time that Hb and Hct are in therapeutic levels in both treatment groups indicates that developing a precise targeted-therapy to eliminate cancer cells along with an effective treatment for CRA, as we presented here, could bring important clinical benefits.