Abstract
Purpose
Intraperitoneal (IP) injection of mesenchymal stem cells (MSCs) has been reported to treat colitis in mice. Complications such as abdominal organ injury and infection are significant concerns. We studied a single injection of human umbilical cord MSCs (hUCMSCs) via the subcutaneous (SC) and IP routes in mice with colitis.
Methods
Male C57BL/6Ncrl mice were divided into control, phosphate-buffered saline (PBS), hUCMSCs SC, and hUCMSCs IP injection groups. Colitis was induced by 3% dextran sulfate sodium (DSS). The disease activity index (DAI), colon length, histology, inflammation score, cytokine and chemokine staining and in vivo stem cell images were recorded.
Results
The DAI in the SC group was significantly lower than that in the IP group during late acute colitis. The colon was significantly shorter, and the colon inflammation score was significantly higher in the PBS group than the control group. There were no significant differences in the colon length and inflammation score between the control group and the SC and IP groups. The expressions of IL17A and Gro-α decreased in the SC group compared with those in the IP group on the 8th and 25th days. hUCMSCs via SC injection accumulated in the subcutaneous tissue to the 25th day.
Conclusion
hUCMSCs via SC and IP injection reduced DSS-induced acute colitis and decreased progression to chronic colitis. The anti-inflammatory effects of hUCMSCs were better in the SC injection group than the IP injection group. In clinical practice in humans, SC injection of hUCMSCs is relatively safer and more convenient than IP injection.
Similar content being viewed by others
References
Abraham, C., & Cho, J. H. (2009). Inflammatory bowel disease. The New England Journal of Medicine,361(21), 2066–2078. https://doi.org/10.1056/NEJMra0804647.
Zhang, Y. Z., & Li, Y. Y. (2014). Inflammatory bowel disease: Pathogenesis. World Journal of Gastroenterology,20(1), 91–99. https://doi.org/10.3748/wjg.v20.i1.91.
Loftus, E. V., Jr. (2004). Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology,126(6), 1504–1517.
Garcia-Bosch, O., Ricart, E., & Panes, J. (2010). Review article: Stem cell therapies for inflammatory bowel disease—Efficacy and safety. Alimentary Pharmacology & Therapeutics,32(8), 939–952. https://doi.org/10.1111/j.1365-2036.2010.04439.x.
Lightner, A. L. (2017). Stem cell therapy for inflammatory bowel disease. Clinical and Translational Gastroenterology,8(3), e82. https://doi.org/10.1038/ctg.2017.7.
Lee, H. J., Oh, S. H., Jang, H. W., Kwon, J. H., Lee, K. J., Kim, C. H., et al. (2016). Long-term effects of bone marrow-derived mesenchymal stem cells in dextran sulfate sodium-induced murine chronic colitis. Gut and Liver,10(3), 412–419. https://doi.org/10.5009/gnl15229.
Peyrin-Biroulet, L., Loftus, E. V., Jr., Colombel, J. F., & Sandborn, W. J. (2010). The natural history of adult Crohn's disease in population-based cohorts. The American Journal of Gastroenterology,105(2), 289–297. https://doi.org/10.1038/ajg.2009.579.
Wallace, K. L., Zheng, L. B., Kanazawa, Y., & Shih, D. Q. (2014). Immunopathology of inflammatory bowel disease. World Journal of Gastroenterology,20(1), 6–21. https://doi.org/10.3748/wjg.v20.i1.6.
Iida, N., & Grotendorst, G. R. (1990). Cloning and sequencing of a new gro transcript from activated human monocytes: Expression in leukocytes and wound tissue. Molecular and Cellular Biology,10(10), 5596–5599.
Uguccioni, M., D'Apuzzo, M., Loetscher, M., Dewald, B., & Baggiolini, M. (1995). Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. European Journal of Immunology,25(1), 64–68. https://doi.org/10.1002/eji.1830250113.
Ohtsuka, Y., Lee, J., Stamm, D. S., & Sanderson, I. R. (2001). MIP-2 secreted by epithelial cells increases neutrophil and lymphocyte recruitment in the mouse intestine. Gut,49(4), 526–533.
Paplinska, M., Grubek-Jaworska, H., & Chazan, R. (2007). Role of eotaxin in the pathophysiology of asthma. Pneumonologia i alergologia polska,75(2), 180–185.
Chang, Y. L., Lo, H. Y., Cheng, S. P., Chang, K. T., Lin, X. F., Lee, S. P., et al. (2019). Therapeutic effects of a single injection of human umbilical mesenchymal stem cells on acute and chronic colitis in mice. Scientific Reports,9(1), 5832. https://doi.org/10.1038/s41598-019-41910-x.
Phinney, D. G., & Prockop, D. J. (2007). Concise review: Mesenchymal stem/multipotent stromal cells: The state of transdifferentiation and modes of tissue repair–current views. Stem Cells,25(11), 2896–2902. https://doi.org/10.1634/stemcells.2007-0637.
De Miguel, M. P., Fuentes-Julian, S., Blazquez-Martinez, A., Pascual, C. Y., Aller, M. A., Arias, J., et al. (2012). Immunosuppressive properties of mesenchymal stem cells: Advances and applications. Current Molecular Medicine,12(5), 574–591.
Batsali, A. K., Kastrinaki, M. C., Papadaki, H. A., & Pontikoglou, C. (2013). Mesenchymal stem cells derived from Wharton's Jelly of the umbilical cord: Biological properties and emerging clinical applications. Current Stem Cell Research & Therapy,8(2), 144–155.
Li, T., Xia, M., Gao, Y., Chen, Y., & Xu, Y. (2015). Human umbilical cord mesenchymal stem cells: An overview of their potential in cell-based therapy. Expert Opinion on Biological Therapy,15(9), 1293–1306. https://doi.org/10.1517/14712598.2015.1051528.
Wu, K. H., Chan, C. K., Tsai, C., Chang, Y. H., Sieber, M., Chiu, T. H., et al. (2011). Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation,91(12), 1412–1416. https://doi.org/10.1097/TP.0b013e31821aba18.
He, X. W., He, X. S., Lian, L., Wu, X. J., & Lan, P. (2012). Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Digestive Diseases and Sciences,57(12), 3136–3144. https://doi.org/10.1007/s10620-012-2290-5.
Kim, H. S., Shin, T. H., Lee, B. C., Yu, K. R., Seo, Y., Lee, S., et al. (2013). Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology, 145(6), 1392–1403 e1391–1398. https://doi.org/10.1053/j.gastro.2013.08.033.
Lin, Y., Lin, L., Wang, Q., Jin, Y., Zhang, Y., Cao, Y., et al. (2015). Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium-induced colitis in mice. Clinical and Experimental Pharmacology & Physiology,42(1), 76–86. https://doi.org/10.1111/1440-1681.12321.
Liang, L., Dong, C., Chen, X., Fang, Z., Xu, J., Liu, M., et al. (2011). Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid (TNBS)-induced colitis. Cell Transplantation,20(9), 1395–1408. https://doi.org/10.3727/096368910X557245.
Banerjee, A., Bizzaro, D., Burra, P., Di Liddo, R., Pathak, S., Arcidiacono, D., et al. (2015). Umbilical cord mesenchymal stem cells modulate dextran sulfate sodium induced acute colitis in immunodeficient mice. Stem Cell Research & Therapy,6, 79. https://doi.org/10.1186/s13287-015-0073-6.
Sun, T., Gao, G. Z., Li, R. F., Li, X., Li, D. W., Wu, S. S., et al. (2015). Bone marrow-derived mesenchymal stem cell transplantation ameliorates oxidative stress and restores intestinal mucosal permeability in chemically induced colitis in mice. American Journal of Translational Research,7(5), 891–901.
Wang, M., Liang, C., Hu, H., Zhou, L., Xu, B., Wang, X., et al. (2016). Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Scientific Reports,6, 30696. https://doi.org/10.1038/srep30696.
Lee, M. J., Yoon, T. G., Kang, M., Kim, H. J., & Kang, K. S. (2017). Effect of subcutaneous treatment with human umbilical cord blood-derived multipotent stem cells on peripheral neuropathic pain in rats. The Korean Journal of Physiology & Pharmacology,21(2), 153–160. https://doi.org/10.4196/kjpp.2017.21.2.153.
Kim, S. W., Han, H., Chae, G. T., Lee, S. H., Bo, S., Yoon, J. H., et al. (2006). Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells,24(6), 1620–1626. https://doi.org/10.1634/stemcells.2005-0365.
Melgar, S., Karlsson, A., & Michaelsson, E. (2005). Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: Correlation between symptoms and inflammation. American Journal of Physiology,288(6), G1328–1338. https://doi.org/10.1152/ajpgi.00467.2004.
Chan, C. K., Wu, K. H., Lee, Y. S., Hwang, S. M., Lee, M. S., Liao, S. K., et al. (2012). The comparison of interleukin 6-associated immunosuppressive effects of human ESCs, fetal-type MSCs, and adult-type MSCs. Transplantation,94(2), 132–138. https://doi.org/10.1097/TP.0b013e31825940a4.
Hall, L. J., Faivre, E., Quinlan, A., Shanahan, F., Nally, K., & Melgar, S. (2011). Induction and activation of adaptive immune populations during acute and chronic phases of a murine model of experimental colitis. Digestive Diseases and Sciences,56(1), 79–89. https://doi.org/10.1007/s10620-010-1240-3.
O'Carroll, C., Moloney, G., Hurley, G., Melgar, S., Brint, E., Nally, K., et al. (2013). Bcl-3 deficiency protects against dextran-sodium sulphate-induced colitis in the mouse. Clinical and Experimental Immunology,173(2), 332–342. https://doi.org/10.1111/cei.12119.
Siegmund, B., Rieder, F., Albrich, S., Wolf, K., Bidlingmaier, C., Firestein, G. S., et al. (2001). Adenosine kinase inhibitor GP515 improves experimental colitis in mice. Journal of Pharmacology and Experimental Therapeutics,296(1), 99–105.
Erben, U., Loddenkemper, C., Doerfel, K., Spieckermann, S., Haller, D., Heimesaat, M. M., et al. (2014). A guide to histomorphological evaluation of intestinal inflammation in mouse models. International Journal of Clinical and Experimental Pathology,7(8), 4557–4576.
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012). NIH Image to ImageJ: 25 years of image analysis. Nature Methods,9(7), 671–675.
Kalchenko, V., Shivtiel, S., Malina, V., Lapid, K., Haramati, S., Lapidot, T., et al. (2006). Use of lipophilic near-infrared dye in whole-body optical imaging of hematopoietic cell homing. Journal of Biomedical Optics,11(5), 050507. https://doi.org/10.1117/1.2364903.
Song, J. Y., Kang, H. J., Hong, J. S., Kim, C. J., Shim, J. Y., Lee, C. W., et al. (2017). Umbilical cord-derived mesenchymal stem cell extracts reduce colitis in mice by re-polarizing intestinal macrophages. Scientific Reports,7(1), 9412. https://doi.org/10.1038/s41598-017-09827-5.
Mao, F., Wu, Y., Tang, X., Wang, J., Pan, Z., Zhang, P., et al. (2017). Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease through the regulation of 15-LOX-1 in macrophages. Biotechnology Letters,39(6), 929–938. https://doi.org/10.1007/s10529-017-2315-4.
Hocking, A. M. (2015). The role of chemokines in mesenchymal stem cell homing to wounds. Advances in Wound Care,4(11), 623–630. https://doi.org/10.1089/wound.2014.0579.
Kean, T. J., Lin, P., Caplan, A. I., & Dennis, J. E. (2013). MSCs: Delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells International,2013, 732742. https://doi.org/10.1155/2013/732742.
Becker, S., Quay, J., Koren, H. S., & Haskill, J. S. (1994). Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. The American Journal of Physiology,266(3 Pt 1), L278–286. https://doi.org/10.1152/ajplung.1994.266.3.L278.
Moser, B., Clark-Lewis, I., Zwahlen, R., & Baggiolini, M. (1990). Neutrophil-activating properties of the melanoma growth-stimulatory activity. The Journal of Experimental Medicine,171(5), 1797–1802.
Schumacher, C., Clark-Lewis, I., Baggiolini, M., & Moser, B. (1992). High- and low-affinity binding of GRO alpha and neutrophil-activating peptide 2 to interleukin 8 receptors on human neutrophils. Proceedings of the National Academy of Sciences of the United States of America,89(21), 10542–10546.
Acknowledgements
This work was supported by grants from Taoyuan General Hospital, Taiwan (PTH10708 and PTH10709).
Funding
This study was funded by Taoyuan General Hospital, Taiwan (Grant Number: PTH10708 and PTH10709).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical Approval
This work was approved by the institutional review board of Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan (IRB Number: TYGH104043). The research was conducted in accordance with the Helsinki Declaration. All applicable international, national, and institutional guidelines for the care and use of animals were followed. All animal experiments were performed in accordance with the relevant guidelines and regulations of the Animal Ethics Committee of Chung Yuan Christian University (IACUC Approval Number: 106019) accredited for laboratory animal care by the Ministry of Health and Welfare of Taiwan, Republic of China.
Rights and permissions
About this article
Cite this article
Chang, YL., Lo, HY., Cheng, SP. et al. Therapeutic Efficacy of Subcutaneous and Intraperitoneal Injections of a Single Dose of Human Umbilical Mesenchymal Stem Cells in Acute and Chronic Colitis in a Mouse Model. J. Med. Biol. Eng. 40, 82–90 (2020). https://doi.org/10.1007/s40846-019-00494-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40846-019-00494-7
Keywords
- Colitis
- Inflammatory bowel disease
- Mesenchymal stem cells
- Subcutaneous injection
- Intraperitoneal injection