Login Register Cart 0
Generic placeholder image

Current Gene Therapy

Editor-in-Chief

ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Therapeutic Effects of Mesenchymal Stem Cells Expressing Erythropoietin on Cancer-Related Anemia in Mice Model

Author(s): Mohammad Estiri, Bahareh Estiri, Asghar Fallah, Marziyeh Aghazadeh, Amir Sedaqati, Abbas Abdollahi, Mahsa Rabienia, Nahid Mortazavidehkordi and Akbar Farjadfar*

Volume 22, Issue 5, 2022

Published on: 13 May, 2022

Page: [406 - 416] Pages: 11

DOI: 10.2174/1566523222666220405134136

Price: $65

Abstract

Background: Cancer-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, the development of long-lasting and curative therapies is urgently required.

Objective: In this study, a cell and gene therapy strategy was developed for in vivo delivery of EPO cDNA by way of genetic engineering of human Wharton’s jelly mesenchymal stem cells (hWJMSCs) to produce and secrete human EPO protein for extended periods after transplantation into the mice model of CRA.

Methods: To evaluate CRA’s treatment in cancer-free and cancerous conditions, first, a recombinant breast cancer cell line 4T1 which expressed herpes simplex virus type 1 thymidine kinase (HSV1-TK) by a lentiviral vector encoding HSV1-TK was developed and injected into mice. After three weeks, all mice developed metastatic breast cancer associated with acute anemia. Then, ganciclovir (GCV) was administered for ten days in half of the mice to clear cancer cells. Meanwhile, another lentiviral vector encoding EPO to transduce hWJMSCs was developed. Following implantation of rhWJMSCs-EPO in the second group of mice, peripheral blood samples were collected once a week for ten weeks from both groups.

Results: Analysis of peripheral blood samples showed that plasma EPO, hemoglobin (Hb), and hematocrit (Hct) concentrations significantly increased and remained at therapeutic for >10 weeks in both treatment groups.

Conclusion: Data indicated that rhWJMSCs-EPO increased the circulating level of EPO, Hb, and Hct in both mouse subject groups and improved the anemia of cancer in both cancer-free and cancerous mice.

Keywords: Gene therapy, cell therapy, cancer-related anemia, erythropoietin, lentivirus, mesenchymal stem cells.

« Previous Next »
Graphical Abstract

[1]
Madeddu C, Gramignano G, Astara G, et al. Pathogenesis and treatment options of cancer related anemia: perspective for a targeted mechanism-based approach. Front Physiol 2018; 9: 1294.
[http://dx.doi.org/10.3389/fphys.2018.01294] [PMID: 30294279]
[2]
Sankaran VG, Weiss MJ. Anemia: progress in molecular mechanisms and therapies. Nat Med 2015; 21(3): 221-30.
[http://dx.doi.org/10.1038/nm.3814] [PMID: 25742458]
[3]
Abdel-Razeq H, Hashem H. Recent update in the pathogenesis and treatment of chemotherapy and cancer induced anemia. Crit Rev Oncol Hematol 2020; 145: 102837.
[http://dx.doi.org/10.1016/j.critrevonc.2019.102837] [PMID: 31830663]
[4]
Debeljak N, Solár P, Sytkowski AJ. Erythropoietin and cancer: The unintended consequences of anemia correction. Front Immunol 2014; 5: 563.
[http://dx.doi.org/10.3389/fimmu.2014.00563] [PMID: 25426117]
[5]
Salamin O, Kuuranne T, Saugy M, Leuenberger N. Erythropoietin as a performance-enhancing drug: Its mechanistic basis, detection, and potential adverse effects. Mol Cell Endocrinol 2018; 464: 75-87.
[http://dx.doi.org/10.1016/j.mce.2017.01.033] [PMID: 28119134]
[6]
Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther 2020; 28(3): 709-22.
[http://dx.doi.org/10.1016/j.ymthe.2020.01.001] [PMID: 31968213]
[7]
Shomali N, Gharibi T, Vahedi G, et al. Mesenchymal stem cells as carrier of the therapeutic agent in the gene therapy of blood disorders. J Cell Physiol 2020; 235(5): 4120-34.
[http://dx.doi.org/10.1002/jcp.29324] [PMID: 31691976]
[8]
Buzhor E, Leshansky L, Blumenthal J, et al. Cell-based therapy approaches: The hope for incurable diseases. Regen Med 2014; 9(5): 649-72.
[http://dx.doi.org/10.2217/rme.14.35] [PMID: 25372080]
[9]
Conrad C, Gupta R, Mohan H, et al. Genetically engineered stem cells for therapeutic gene delivery. Curr Gene Ther 2007; 7(4): 249-60.
[http://dx.doi.org/10.2174/156652307781369119] [PMID: 17969558]
[10]
Gharbavi M, Sharafi A, Ghanbarzadeh S. Mesenchymal stem cells: A new generation of therapeutic agents as vehicles in gene therapy. Curr Gene Ther 2020; 20(4): 269-84.
[http://dx.doi.org/10.2174/1566523220666200607190339] [PMID: 32515309]
[11]
Titov A, Zmievskaya E, Ganeeva I, et al. Adoptive immunotherapy beyond CAR T-cells. Cancers (Basel) 2021; 13(4): 743.
[http://dx.doi.org/10.3390/cancers13040743] [PMID: 33670139]
[12]
Wei W, Huang Y, Li D, Gou H-F, Wang W. Improved therapeutic potential of MSCs by genetic modification. Gene Ther 2018; 25(8): 538-47.
[http://dx.doi.org/10.1038/s41434-018-0041-8] [PMID: 30254305]
[13]
Wei D, Hou J, Zheng K, et al. Suicide gene therapy against malignant gliomas by the local delivery of genetically engineered umbilical cord mesenchymal stem cells as cellular vehicles. Curr Gene Ther 2019; 19(5): 330-41.
[http://dx.doi.org/10.2174/1566523219666191028103703] [PMID: 31657679]
[14]
Musiał-Wysocka A, Kot M, Majka M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant 2019; 28(7): 801-12.
[http://dx.doi.org/10.1177/0963689719837897] [PMID: 31018669]
[15]
Liu J, Han D, Wang Z, et al. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy 2013; 15(2): 185-91.
[http://dx.doi.org/10.1016/j.jcyt.2012.09.005] [PMID: 23321330]
[16]
Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24(5): 1294-301.
[http://dx.doi.org/10.1634/stemcells.2005-0342] [PMID: 16410387]
[17]
Hosseini A, Estiri H, Niaki HA, Alizadeh A, Zadeh BA, Ghaderian SMH, et al. Multiple sclerosis gene therapy using recombinant viral vectors: Overexpression of IL-4, IL-10 and leukemia inhibitory factor in Wharton’s jelly stem cells in the EAE mice model. Cell J (Yakhteh) 2017; 19(3): 361.
[PMID: 28836399]
[18]
Can A, Celikkan FT, Cinar O. Umbilical cord mesenchymal stromal cell transplantations: A systemic analysis of clinical trials. Cytotherapy 2017; 19(12): 1351-82.
[http://dx.doi.org/10.1016/j.jcyt.2017.08.004] [PMID: 28964742]
[19]
Wang C, Chen YG, Gao JL, et al. Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model. Oncol Lett 2015; 10(2): 754-60.
[http://dx.doi.org/10.3892/ol.2015.3304] [PMID: 26622565]
[20]
Shi Q, Gao J, Jiang Y, et al. Differentiation of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells into endometrial cells. Stem Cell Res Ther 2017; 8(1): 246.
[http://dx.doi.org/10.1186/s13287-017-0700-5] [PMID: 29096715]
[21]
Robert AW, Marcon BH, Dallagiovanna B, Shigunov P. Adipogenesis, osteogenesis, and chondrogenesis of human mesenchymal stem/stromal cells: a comparative transcriptome approach. Front Cell Dev Biol 2020; 8: 561.
[http://dx.doi.org/10.3389/fcell.2020.00561] [PMID: 32733882]
[22]
Fathi E, Farahzadi R, Vietor I, Javanmardi S. Cardiac differentiation of bone-marrow-resident c-kit+ stem cells by L-carnitine increases through secretion of VEGF, IL6, IGF-1, and TGF- β as clinical agents in cardiac regeneration. J Biosci 2020; 45(1): 1-11.
[http://dx.doi.org/10.1007/s12038-020-00063-0] [PMID: 32713855]
[23]
Fathi E, Farahzadi R, Valipour B. Alginate/gelatin encapsulation promotes NK cells differentiation potential of bone marrow resident C-kit+ hematopoietic stem cells. Int J Biol Macromol 2021; 177: 317-27.
[http://dx.doi.org/10.1016/j.ijbiomac.2021.02.131] [PMID: 33621568]
[24]
Kim A, Rivera S, Shprung D, et al. Mouse models of anemia of cancer. PLoS One 2014; 9(3): e93283.
[http://dx.doi.org/10.1371/journal.pone.0093283] [PMID: 24681760]
[25]
Liu M, Jin X, He X, Pan L, Zhang X, Zhao Y. Macrophages support splenic erythropoiesis in 4T1 tumor-bearing mice. PLoS One 2015; 10(3): e0121921.
[http://dx.doi.org/10.1371/journal.pone.0121921] [PMID: 25822717]
[26]
Majumdar AS, Zolotorev A, Samuel S, et al. Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model. Cancer Gene Ther 2000; 7(7): 1086-99.
[http://dx.doi.org/10.1038/sj.cgt.7700215] [PMID: 10917212]
[27]
Eliopoulos N, Gagnon RF, Francois M, Galipeau J. Erythropoietin delivery by genetically engineered bone marrow stromal cells for correction of anemia in mice with chronic renal failure. J Am Soc Nephrol 2006; 17(6): 1576-84.
[http://dx.doi.org/10.1681/ASN.2005101035] [PMID: 16672321]
[28]
Johnston J, Tazelaar J, Rivera VM, Clackson T, Gao G-P, Wilson JM. Regulated expression of erythropoietin from an AAV vector safely improves the anemia of β-thalassemia in a mouse model. Mol Ther 2003; 7(4): 493-7.
[http://dx.doi.org/10.1016/S1525-0016(03)00043-1] [PMID: 12727112]
[29]
Fabre EE, Bigey P, Beuzard Y, Scherman D, Payen E. Careful adjustment of Epo non-viral gene therapy for β-thalassemic anaemia treatment. Genet Vaccines Ther 2008; 6(1): 10.
[http://dx.doi.org/10.1186/1479-0556-6-10] [PMID: 18334017]
[30]
Ma C, Fan Z, Gao Z, Wang S, Shan Z. Delivery of human erythropoietin gene with an adeno-associated virus vector through parotid glands to treat renal anaemia in a swine model. Gene Ther 2017; 24(11): 692-8.
[http://dx.doi.org/10.1038/gt.2017.70] [PMID: 28753201]
[31]
Zaiss AK, Muruve DA. Immune responses to adeno-associated virus vectors. Curr Gene Ther 2005; 5(3): 323-31.
[http://dx.doi.org/10.2174/1566523054065039] [PMID: 15975009]
[32]
Roth JC, Curiel DT, Pereboeva L. Cell vehicle targeting strategies. Gene Ther 2008; 15(10): 716-29.
[http://dx.doi.org/10.1038/gt.2008.38] [PMID: 18369326]
[33]
Lin R-Z, Dreyzin A, Aamodt K, et al. Induction of erythropoiesis using human vascular networks genetically engineered for controlled erythropoietin release. Blood 2011; 118(20): 5420-8.
[http://dx.doi.org/10.1182/blood-2011-08-372946] [PMID: 21937702]
[34]
Scheibe F, Gladow N, Mergenthaler P, et al. Nonviral gene delivery of erythropoietin by mesenchymal stromal cells. Gene Ther 2012; 19(5): 550-60.
[http://dx.doi.org/10.1038/gt.2011.139] [PMID: 21956691]
[35]
Lee K, Lee N, Shin E, Chang J, Na D, Lee J. Enhancing the therapeutic potential of mesenchymal stem cell-based therapy via CRISPR/Cas9-based genome editing. Cytotherapy 2020; 22(5): S15.
[http://dx.doi.org/10.1016/j.jcyt.2020.03.480]
[36]
Hamidian Jahromi S, Davies JE. Concise review: Skeletal muscle as a delivery route for mesenchymal stromal cells. Stem Cells Transl Med 2019; 8(5): 456-65.
[http://dx.doi.org/10.1002/sctm.18-0208] [PMID: 30720934]
[37]
Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, et al. Human erythropoietin gene therapy for patients with chronic renal failure. Blood 2005; 106(7): 2280-6.
[http://dx.doi.org/10.1182/blood-2004-11-4174] [PMID: 15798000]
[38]
Macieira-Coelho A. Slowing down of the cell cycle during fibroblast proliferationCellular Ageing and Replicative Senescence. Springer 2016; pp. 29-47.

Rights & Permissions Print Cite
Article Metrics
14
© 2024 Bentham Science Publishers | Privacy Policy