Abstract
Inflammatory bowel disease (IBD) belongs to the group of diseases characterized by idiopathic inflammation of the gastrointestinal organs. Two basic IBD types are distinguished: ulcerative colitis and Crohn’s disease. The IBD symptoms including vomiting and diarrhea, abdominal pain, rectal hemorrhage, and anemia have a significant negative impact on the general patient’s state of health. More than four million people in the USA and Europe suffer from IBD, while the general incidence of this disease in the developed countries exceeds 0.5% of the population. Besides, IBD is associated with a significant risk of colitis-associated malignancy. In the last decades, considerable progress has been achieved in the IBD therapy due to application of drugs suppressing the local gastrointestinal tract inflammation, such as antibodies to TNF-α (infliximab and adalimumab), corticosteroids, salicylates, etc. At the same time, this strategy, unfortunately, does not result in the repair of the damaged tissues, primarily ulcers of the colon, in many IBD patients. To achieve the mucosa healing and stable remission in IBD patients, novel approaches are required, cell therapy, actively used since the beginning of 2000s, being one of them. In our book chapter, we discuss the advantages and problems of application of mesenchymal stem cells (MSCs) which are most actively used in the cell therapy of IBD. The results of the most important preclinical and clinical studies are covered.
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Abbreviations
- 5-АSA:
-
5-Aminosalicylic acid
- APC:
-
Antigen-presenting cells
- ASC:
-
Adipose tissue–derived stem cells
- AZA:
-
Azathioprine
- BM:
-
Bone marrow
- CCL-2:
-
С-С-chemokine ligand 2
- CD:
-
Crohn’s disease
- CDAI:
-
Crohn’ Disease Activity Index
- CI:
-
Confidence interval
- DC:
-
Dendritic cells
- DSS:
-
Dextran sodium sulfate
- GCS:
-
Glucocorticosteroids
- GI:
-
Gastrointestinal
- HBI:
-
Harvey-Bradshaw Index
- HGF:
-
Hepatocyte growth factor
- HLA-G:
-
Human leukocyte antigen-G
- hUC:
-
Human umbilical cord
- I/A:
-
Intra-arterial
- I/V:
-
Intravenous
- IBD:
-
Inflammatory bowel disease
- IBDQ:
-
Inflammatory Bowel Disease Questionnaire
- ICG:
-
Lindocyanine green
- IDO:
-
Indoleamine-2,3-dioxygenase
- IFN:
-
Interferon
- IL:
-
Interleukin
- iNOS:
-
Inducible nitric oxide synthase
- LPS:
-
Lipopolysaccharide
- MHC:
-
Major histocompatibility complex
- miR:
-
MicroRNA
- MMP:
-
Matrix metalloproteinases
- MSCs:
-
Mesenchymal stem cells
- NK-cells:
-
Natural killer cells
- PDAI:
-
Perianal Disease Activity Index
- PGE2:
-
Prostaglandin E2
- PSC:
-
Primary sclerosing cholangitis
- RR:
-
Relative risk
- SMA:
-
Smooth muscle actin
- SVF:
-
Stromal vascular fraction
- TGF-β:
-
β-transforming growth factor
- TNBS:
-
Trinitrobenzenesulfonic acid
- TNF:
-
Tumor necrosis factor
- UC:
-
Ulcerative colitis
References
Ahluwalia B, Moraes L, Magnusson MK, Öhman L (2018) Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol 53:379–389. https://doi.org/10.1080/00365521.2018.1447597
Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T et al (2012) Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10(5):544–555. https://doi.org/10.1016/j.stem.2012.03.007
Barnhoorn MC, Wasser MNJM, Roelofs H, Maljaars PWJ, Molendijk I, Bonsing BA, Oosten LEM et al (2020) Long-term evaluation of allogeneic bone marrow-derived mesenchymal stromal cell therapy for Crohn’s disease perianal fistulas. J Crohns Colitis 14(1):64–70. https://doi.org/10.1093/ecco-jcc/jjz116
Bernardo ME, Fibbe WE (2013) Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13(4):392–402. https://doi.org/10.1016/j.stem.2013.09.006
Buccini S, Haider KH, Ahmed RPH, Jiang S, Ashraf M (2012) Cardiac progenitors derived from reprogrammed mesenchymal stem cells contribute to angiomyogenic repair of the infarcted heart. Basic Res Cardiol 107(6):301–314
Cao Y, Su Q, Zhang B, Shen F, Li S (2021) Efficacy of stem cells therapy for Crohn’s fistula: a meta-analysis and systematic review. Stem Cell Res Ther 12(1):32. https://doi.org/10.1186/s13287-020-02095-7
Caplan AI (2016) MSCss: the sentinel and safe-guards of injury. J Cell Physiol 231(7):1413–1416. https://doi.org/10.1002/jcp.25255
Caplan AI, Correa D (2011) The MSCs: an injury drugstore. Cell Stem Cell 9(1):11–15. https://doi.org/10.1016/j.stem.2011.06.008
Cassinotti A, Passamonti F, Segato S (2012) Cell therapy in inflammatory bowel disease. Pharmacol Res 163:2021,105247. https://doi.org/10.1016/j.phrs.2020.105247
CCFA (The Crohn’s & Colitis Foundation of America) (2014) The facts about inflammatory bowel diseases. https://www.crohnscolitisfoundation.org/sites/default/files/2019-02/Updated%20IBD%20Factbook.pdf
Chen QQ, Yan L, Wang CZ, Wang WH, Shi H, Su BB, Zeng QH et al (2013) Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. World J Gastroenterol 19(29):4702–4717. https://doi.org/10.3748/wjg.v19.i29.4702
Cho YB, Park KJ, Yoon SN, Song KH, Kim DS, Jung SH, Kim M et al (2015) Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med 4(5):532–537. https://doi.org/10.5966/sctm.2014-0199
de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A (2013) Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Color Dis 28(3):313–323. https://doi.org/10.1007/s00384-012-1581-9
Dias CB, Milanski M, Portovedo M, Horita V, Ayrizono Mde L, Planell N, Coy CS et al (2014) Defective apoptosis in intestinal and mesenteric adipose tissue of Crohn's disease patients. PLoS One 9(6):e98547. https://doi.org/10.1371/journal.pone.0098547
Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, Lightner AL, Dave M et al (2017) Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn’s disease. Gastroenterology 153(1):59–62.e2. https://doi.org/10.1053/j.gastro.2017.04.001
GBD 2017 Inflammatory Bowel Disease Collaborators (2020) The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 5(1):17–30. https://doi.org/10.1016/S2468-1253(19)30333-4
Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D (2010) Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 1(1):2. https://doi.org/10.1186/scrt2
Gronthos S, Arthur A, Bartold PM, Shi S (2011) A method to isolate and culture expand human dental pulp stem cells. Methods Mol Biol 698:107–121. https://doi.org/10.1007/978-1-60761-999-4_9
Guindi M, Riddell RH (2004) Indeterminate colitis. J Clin Pathol 57(12):1233–1244. https://doi.org/10.1136/jcp.2003.015214
Haider KH (2018) The aging stem cells and cardiac reparability: lesson learnt from clinical studies is that old is not always gold. Regen Med 13(4):457–475
Haider KH, Aramini B (2020) Mircrining the injured heart with stem cell-derived exosomes: an emerging strategy of cell-free therapy. Stem Cell Res Ther 11(1):23. https://doi.org/10.1186/s13287-019-1548-7
Haider KH, Jiang S, Niagara MI, Ashraf M (2008) IGF-I over expressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair. Circ Res 103:1300–1308
Haider KH, Igura K, Ashraf M (2011) Revascor, an injectable formulation of allogeneic, adult mesenchymal precursor cells for the treatment of cardiovascular diseases. Curr Opin Mol Ther 2011
Han X, Ding S, Jiang H, Liu G (2021) Roles of macrophages in the development and treatment of gut inflammation. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2021.625423
Herreros MD, Garcia-Olmo D, Guadalajara H, Georgiev-Hristov T, Brandariz L, Garcia-Arranz M (2019) Stem cell therapy: a compassionate use program in perianal fistula. Stem Cells Int 6132340. https://doi.org/10.1155/2019/6132340
Hidalgo-Garcia L, Galvez J, Rodriguez-Cabezas ME, Anderson PO (2018) Can a conversation between mesenchymal stromal cells and macrophages solve the crisis in the inflamed intestine? Front Pharmacol 9:179. https://doi.org/10.3389/fphar.2018.00179
Hosseini SM, Sani M, Haider KH, Dorvash MR, Ziaee SM, Karimi A (2018) Concomitant use of mesenchymal stem cells and neural stem cells for treatment of spinal cord injury: a combo cell therapy approach. Neurosci Lett 668:138–146
Hu J, Zhao G, Zhang L, Qiao C, Di A, Gao H, Xu H (2016) Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis. Exp Ther Med 12(5):2983–2989. https://doi.org/10.3892/etm.2016.3724
Irhimeh MR, Cooney J (2016) Management of inflammatory bowel disease using stem cell therapy. Curr Stem Cell Res Ther 11(1):72–77. https://doi.org/10.2174/1574888x10666150728121738
Jiang S, Haider KH, Niagara MI, Salim A, Ashraf M (2006) Supportive interaction between cell survival signaling and angio-competent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. Circ Res 99:776–784
Jo H, Eom YW, Kim HS, Park HJ, Kim HM, Cho MY (2018) Regulatory dendritic cells induced by mesenchymal stem cells ameliorate dextran sodium sulfate-induced chronic colitis in mice. Gut Liver 12(6):664–673. https://doi.org/10.5009/gnl18072
Khor B, Gardet A, Xavier RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474(7351):307–317. https://doi.org/10.1038/nature10209
Knyazev OV, Parfenov AI, Konoplyannikov AG, Kagramanova AV, Churikova AA, Ruchkina IN, Lishinskaya AA et al (2015) Safety of mesenchymal stem cells therapy in patients with inflammatory bowel diseases – 5 year follow-up. J Biotechnol Biomater 5:192. https://doi.org/10.4172/2155-952X.1000192
Knyazev OV, Parfenov AI, Konoplyannikov AG, Boldyreva ON (2016) Use of mesenchymal stem cells in the combination therapy of ulcerative colitis. Ter Arkh 88(2):44–48. https://doi.org/10.17116/terarkh201688244-48
Knyazev OV, Kagramanova AV, Fadeeva NA, Lishchinskaya AA, Boldyreva ON, Noskova KK, Gudkova RB et al (2018a) Mesenchymal stromal cells of bone marrow and azathioprine in Crohn’s disease therapy. Ter Arkh 90(2):47–52. https://doi.org/10.26442/terarkh201890247-52
Knyazev OV, Fadeeva NA, Kagramanova AV, Belyakov NI, Orlova NV, Lishchinskaya AA, Konoplyannikov AG et al (2018b) Stem cell therapy for perianal Crohn’s disease. Ter Arkh 90(3):60–66. https://doi.org/10.26442/terarkh201890360-66
Ko JZ, Johnson S, Dave M (2021) Efficacy and safety of mesenchymal stem/stromal cell therapy for inflammatory bowel diseases: an up-to-date systematic review. Biomol Ther 11(1):82. https://doi.org/10.3390/biom11010082
Lazebnik LB, Konopliannikov AG, Kniazev OV, Parfenov AI, Tsaregorodtseva TM, Ruchkina IN, Khomeriki SG et al (2010) Use of allogeneic mesenchymal stem cells in the treatment of intestinal inflammatory diseases. Ter Arkh 82(2):38–43
Lei Y, Haider KH, Sim EKW (2006) Adult stem cells for cardiac repair: a choice between skeletal myoblasts and bone marrow stem cells. Exp Biol Med 231:8–11
Liu J, Liu Q, Chen X (2020) The immunomodulatory effects of mesenchymal stem cells on regulatory B cells. Front Immunol 11:1843. https://doi.org/10.3389/fimmu.2020.01843
Lopez-Santalla M, Hervas-Salcedo R, Fernandez-Garcia M, Bueren JA, Garin MI (2020) Cell therapy with mesenchymal stem cells induces an innate immune memory response that attenuates experimental colitis in the long term. J Crohn’s Colitis 14(10):1424–1435. https://doi.org/10.1093/ecco-jcc/jjaa079
Lv FJ, Tuan RS, Cheung KM, Leung VY (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32(6):1408–1419. https://doi.org/10.1002/stem.1681
Maacha S, Sidahmed H, Jacob S, Gentilcore G, Calzone R, Grivel JC, Cugno C (2020) Paracrine mechanisms of mesenchymal stromal cells in angiogenesis. Stem Cells Int 2020:4356359. https://doi.org/10.1155/2020/4356359
Magro F, Portela F (2010) Management of Inflammatory bowel disease with infliximab and other anti-tumor necrosis factor alpha therapies. BioDrugs 24:3–14. https://doi.org/10.2165/11586290-000000000-00000
Mao F, Wu Y, Tang X, Kang J, Zhang B, Yan Y, Qian H et al (2017) Exosomes derived from human umbilical cord mesenchymal stem cells relieve inflammatory bowel disease in mice. Biomed Res Int:5356760. https://doi.org/10.1155/2017/5356760
Mendt M, Rezvani K, Shpall E (2019) Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant 54(Suppl 2):789–792. https://doi.org/10.1038/s41409-019-0616-z
Mianehsaz E, Mirzaei HR, Mahjoubin-Tehran M, Rezaee A, Sahebnasagh R, Pourhanifeh MH, Mirzaei H et al (2019) Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther 10(1):340. https://doi.org/10.1186/s13287-019-1445-0
Ocansey DKW, Qiu W, Wang J, Yan Y, Qian H, Zhang X, Xu W, Mao F (2020) The achievements and challenges of mesenchymal stem cell-based therapy in inflammatory bowel disease and its associated colorectal cancer. Stem Cells Int. 7819824, 18 pp. https://doi.org/10.1155/2020/7819824
Ommer A, Herold A, Joos A, Schmidt C, Weyand G, Bussen D (2012) Gore BioA fistula plug in the treatment of high anal fistulas – initial results from a German multicenter-study. Ger Med Sci 10:Doc13. https://doi.org/10.3205/000164
Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A et al (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388(10051):1281–1290. https://doi.org/10.1016/S0140-6736(16)31203-X
Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A et al (2018) Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology 154(5):1334–1342.e4. https://doi.org/10.1053/j.gastro.2017.12.020
Prockop DJ (2009) Repair of tissues by adult stem/progenitor cells (MSCss): controversies, myths, and changing paradigms. Mol Ther 17(6):939–946. https://doi.org/10.1038/mt.2009.62
Sairenji T, Collins KL, Evans DV (2017) An update on inflammatory bowel disease. Prim Care 44(4):673–692. https://doi.org/10.1016/j.pop.2017.07.010
Samoylova EM, Kalsin VA, Bespalova VA, Devichensky VM, Baklaushev VP (2017) Exosomes: from biology to clinics. Genes Cells XII(4):7–19. https://doi.org/10.23868/201707024
Scott LJ (2018) Darvadstrocel: a review in treatment-refractory complex perianal fistulas in Crohn’s disease. BioDrugs 32(6):627–634. https://doi.org/10.1007/s40259-018-0311-4
Sisakhtnezhad S, Alimoradi E, Akrami H (2017) External factors influencing mesenchymal stem cell fate in vitro. Eur J Cell Biol 96(1):13–33. https://doi.org/10.1016/j.ejcb.2016.11.003
Siyu L, Fei L, You Z, Baeku J, Qiang S, Shu G (2020) Immunosuppressive property of mscs mediated by cell surface receptors. Front Immunol 11:1076. https://doi.org/10.3389/fimmu.2020.01076
Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L (2008) Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111(3):1327–1333. https://doi.org/10.1182/blood-2007-02-074997
Terai S, Tsuchiya A (2017) Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis. J Gastroenterol 52(2):129–140. https://doi.org/10.1007/s00535-016-1258-1
Tolar J, Le Blanc K, Keating A, Blazar BR (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28(8):1446–1455. https://doi.org/10.1002/stem.459
Wang S, Miao Z, Yang Q, Wang Y, Zhang J (2018) The dynamic roles of mesenchymal stem cells in colon cancer. Can J Gastroenterol Hepatol 7628763:8 pp. https://doi.org/10.1155/2018/7628763
Williams JT, Southerland SS, Souza J, Calcutt AF, Cartledge RG (1999) Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes. Am Surg 65(1):22–26
Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K et al (2009) Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 218(3):350–359. https://doi.org/10.1002/path.2535
Yang R, Huang H, Cui S, Zhou Y, Zhang T, Zhou Y (2020) IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b. Cell Death Dis 11(7):603. https://doi.org/10.1038/s41419-020-02788-0
Zhang J, Lv S, Liu X, Song B, Shi L (2018) Umbilical cord mesenchymal stem cell treatment for Crohn’s disease: a randomized controlled clinical trial. Gut Liver 12(1):73–78. https://doi.org/10.5009/gnl17035
Zhao T, Sun F, Liu J, Ding T, She J, Mao F, Xu W et al (2019) Emerging role of mesenchymal stem cell-derived exosomes in regenerative medicine. Curr Stem Cell Res Ther 14(6):482–494. https://doi.org/10.2174/1574888X14666190228103230
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7(2):211–228. https://doi.org/10.1089/107632701300062859
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Konoplyannikov, M., Knyazev, O., Timashev, P., Baklaushev, V. (2022). Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease. In: Haider, K.H. (eds) Handbook of Stem Cell Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-16-6016-0_8-1
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