Cell and Organ Transplantology. 2018; 6(2):158-163.
DOI: 10.22494/cot.v6i2.88
The effects of the transplantation of thymus-derived multipotent stromal cells on the immune system and survival of lethally irradiated mice
Nikolska K. I.
State Institute of Genetic and Regenerative Medicine National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
Abstract
The traditional source for regeneration of the immune system is hematopoietic stem cells. Multipotent stromal cells (MSCs), especially MSCs of the thymus, have been significantly less studied for this purpose.
The aim was to study the regenerative, immunobiological and radioprotective properties of thymus-derived multipotent stromal cells.
Materials and methods. Researches were conducted to study the effect of transplantation of thymus-derived MSCs on the survival and features of restoration of the immune system of lethally irradiated mice. Lethally irradiated (with dose 9 Gy) CBA mice, 5-6 weeks old, were injected intravenously with 5·104 thymus-derived MSCs. On the 30th day the cellularity of lymphoid organs, bone marrow and blood, natural and adaptive immunity were studied.
Results. It was found that transplanted thymus-derived MSCs significantly prolonged the survival and average lifespan of mice, restored the cellularity of bone marrow, the ability of bone marrow stromal cells to form fibroblast colonies, greatly increased the cellularity of the thymus and contributed to the normalization of the number of leukocytes in the blood. In addition, the natural cytotoxic activity of splenocytes and their ability to synthesize α/β- and γ-interferons, significantly increased, the number of antibody-producing cells was stimulated and the synthesis of antibodies increased. The concentration of the tumor necrosis factor α in the blood was significantly reduced.
Conclusions. The results indicate that thymus-derived MSCs possess pronounced regenerative and immunobiological activity, which provides these cells with radioprotective ability. The obtained data can be used to develop combined cell transplants and new methods for improving their regenerative potential and radioprotective effects.
Key words: thymus-derived multipotent stromal cells; cell transplantation; regeneration of the immune system; lethal irradiation
Full Text PDF (eng) Full Text PDF (ua)| 1. Chertkov IL, Gurevich OA. Stvolovaya krovetvornaya kletka i ee mikrookruzhenie [Hematopoietic stem cell and its microenvironment]. Moskva: Meditsina – Moscow: Medicine, 1984. 240 p. [In Russian] | ||||
| 2. Nikolskaya EI. Kletochnaya kompozitsiya kostnomozgovykh nish gemopoeticheskikh stvolovykh kletok (obzor literatury) [Cell composition of bone marrow hematopoietic stem cells niches (review)]. Zhurnal Natsіonal’noї Akademії medichnikh nauk Ukraїni – Journal of National Academy of Medical Sciences of Ukraine. 2015; 21(3-4):272-286. [In Russian] | ||||
| 3. Nikolskaya EI, Butenko GM. Structural-functional organization of the bone marrow hematopoietic stem cells niches. Cell and Organ Transplantology. 2016; 4(1):82-100. https://doi.org/10.22494/COT.V4I1.9 |
||||
| 4. Yamauchi Y, Abe K, Mantani A, et al. A novel transgenic technique that allows specific marking of the neural crest cell lineage in mice. Dev. Biol. 1999; 212(1):191-203. https://doi.org/10.1006/dbio.1999.9323 |
||||
| 5. Conway SJ, Henderson DJ, Copp AJ. Pax 3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development. 1997; 124(2):505-514. | ||||
| 6. Takihara Y, Tomotsune D, Shirai M, et al. Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development. 1997; 124(19):3673-3682. | ||||
| 7. Suniara RK, Jenkinson EJ, Owen JJ. An essential role for thymic mesenchyme in early T cell development. J Exp Med. 2000; 191(6):1051-1056. https://doi.org/10.1084/jem.191.6.1051 PMCid:PMC2193125 |
||||
| 8. Itoi M, Tsukamoto N, Yoshida H, Amagai T. Mesenchymal cells are required for functional development of thymic epithelial cells. Int Immunol. 2007; 19(8):953-964. https://doi.org/10.1093/intimm/dxm060 |
||||
| 9. Jenkinson WE, Rossi SW, Parnell SM, et al. PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood. 2007; 109(3):954-960. https://doi.org/10.1182/blood-2006-05-023143 |
||||
| 10. Azghadi SM, Suciu M, Gruia AT, et al. Mesenchymal stromal cells support the viability and differentiation of thymocytes through direct contact in autologous co-cultures. Histochem Cell Biol. 2016; 146(2):153-165. https://doi.org/10.1007/s00418-016-1430-y |
||||
| 11. Jenkinson WE, Jenkinson EJ, Anderson G. Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med. 2003; 198(2):325-332. https://doi.org/10.1084/jem.20022135 PMCid:PMC2194072 |
||||
| 12. Rossi SW, Jeker LT, Ueno T, et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood. 2007; 109(9):3803-3811. https://doi.org/10.1182/blood-2006-10-049767 PMCid:PMC1874572 |
||||
| 13. Chu YW, Schmitz S, Choudhury B, et al. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood. 2008; 112(7):2836-2846. https://doi.org/10.1182/blood-2008-04-149435 PMCid:PMC2556619 |
||||
| 14. Sitnik KM, Kotarsky K, White AJ, et al. Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J. Immunol. 2012; 188(10):4801-4809. https://doi.org/10.4049/jimmunol.1200358 |
||||
| 15. Lax S, Ross EA, White A, et al. CD248 expression on mesenchymal stromal cells is required for post-natal and infectiondependent thymus remodelling and regeneration. FEBS Open Bio. 2012; 2:187-190. https://doi.org/10.1016/j.fob.2012.07.003 PMCid:PMC3642154 |
||||
| 16. Sun L, Sun C, Liang Z, et al. FSP1(+) fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells. Sci Rep. 2015;. 5:14871. https://doi.org/10.1038/srep14871 PMCid:PMC4597222 |
||||
| 17. Patenaude J, Perreault C. Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile. J Immunol. 2016; 196(11):4760-4770. https://doi.org/10.4049/jimmunol.1502499 |
||||
| 18. Nikolsky IS, Nikolskaya VV, Taranukha LI, et al. Radiozashhitnoe dejstvie mul’tipotentnyh stromal’nyh kletok timusa [Radioprotective effect of thymus multipotent stromal cells]. Vestnik Ural’skoy meditsinskoy akademicheskoy nauki – Bull Ural Med Acad. 2009; 24(2/1):84-285. [In Russian] | ||||
| 19. Nikolsky IS, Nikolskaya VV, Demchenko DL, Zubov DO. Potentiation of directed osteogenic differentiation of thymic multipotent stromal cells by prior co-cultivation whith thymocytes. Cell and Organ Transplantology. 2016; 4(2):220-223. https://doi.org/10.22494/cot.v4i2.59 |
||||
| 20. Freshney R Ian. Culture of Animal Cells: A Manual of Basic Technique. Wiley Black Well. 2010. 676 p. https://doi.org/10.1002/9780470649367 |
||||
| 21. Khaitov RM, Pinegin BV, Yarilin AA. Rukovodstvo po klinicheskoy immunologii. Diagnostika zabolevaniy immunnoy sistemy [Guide to clinical immunology. Diagnosis of diseases of the immune system]. Ruk-vo dlya vrachey – A guide for physicians. M.: GEOTAR-Media, 2009. 345 p. | ||||
| 22. Coligan JE, Kruisbeek AM, Margulies DH, et al. Current protocols in immunology. N.Y.: John Wiley and Sons, 2003. P. 4.1.1–4.1.5. | ||||
| 23. Mossman T. Rapid colorimetric assay for cellular growth and survival application to proliferation and cytotoxicity assay. Methods. 1983; 65(1-2):55-63. | ||||
| 24. Stewart WE. Interferon systems.Vienna/New York: Springer,1979. 421 p. https://doi.org/10.1007/978-3-7091-3432-0 |
||||
| 25. Huang M, Yao PW, Chang MD, et al. Identification of anti-inflammatory fractions of Geranium wilfordii using tumor necrosis factor-alpha as a drug target on Herbochip® – an array-based high throughput screening platform. BMC Complement Altern Med. 2015; 15:146. https://doi.org/10.1186/s12906-015-0665-9 PMCid:PMC4443519 |
||||
| 27. Bifari F, Lisi V, Mimiola E, et al. Immune Modulation by Mesenchymal Stem Cells. Transfus Med Hemother. 2008; 35(3):194-204. https://doi.org/10.1159/000128968 PMCid:PMC3083287 |
||||
| 28. Nikolsky IS, Nikolskaya VV, Demchenko DL, et al. Vpliv transplantatsії mul’tipotentnikh stromal’nikh klіtin timusa na іmunnu sistemu mishey v umovakh її regeneratsії [Effect of transplantation of multipotent stromal cells of thymus on the immune system of mice in conditions of its regeneration]. Fіzіologіchniy zhurnal. 2018; 64(4):3-11. https://doi.org/10.15407/fz64.04.003 |
||||
| 29. Wynn RF, Hart CA, Corradi-Perini C, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood. 2004; 104(9):2643-2645. https://doi.org/10.1182/blood-2004-02-0526 |
||||
| 30. Li TS, Shi H, Wang L, Yan C. Effect of Bone Marrow Mesenchymal Stem Cells on Satellite Cell Proliferation and Apoptosis in Immobilization-Induced Muscle Atrophy in Rats. Med Sci Monit. 2016; 22:4651-4660. https://doi.org/10.12659/MSM.898137 PMCid:PMC5132424 |
||||
| 31. Li H, Jiang Y, Jiang X, Guo X, Ning H, Li Y, et al. CCR7 guides migration of mesenchymal stem cell to secondary lymphoid organs: a novel approach to separate GvHD from GvL effect. Stem Cells. 2014; 32(7):1890-1903. https://doi.org/10.1002/stem.1656 |
||||
| 32. Li C, Fu Y, Wang Y, et al. Mesenchymal stromal cells ameliorate acute allergic rhinitis in rats. Cell Biochem Funct. 2017; 35(7):420-425. https://doi.org/10.1002/cbf.3291 PMCid:PMC5698748 |
||||
| 33. Dejbakhsh-Jones S, Jerabek L, Weissman I.L, Strober S. Extrathymic maturation of alpha beta T cells from hemopoietic stem cells. J Immunol. 1995; 155(7):3338–3344. | ||||
| 34. Barda-Saad M, Rozenszajn LA, Globerson A, et al. Selective adhesion of immature thymocytes to bone marrow stromal cells: relevance to T cell lymphopoiesis. Exp Hematol. 1996; 24(2):386-391. | ||||
| 35. Maria OM, Shalaby M, Syme A, et al. Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis. Cytotherapy. 2016; 18(9):1129-1145. https://doi.org/10.1016/j.jcyt.2016.06.008 |
||||
| 36. Li Y, Hisha H, Inaba M, et al. Evidence for migration of donor bone marrow stromal cells into recipient thymus after bone marrow transplantation plus bone grafts: a role of stromal cells in positive selection. Exp Hematol. 2000; 28(8):950-960. https://doi.org/10.1016/S0301-472X(00)00483-5 |
||||
| 37. Wen S, Dooner M, Cheng Y, et al. Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia. 2016; 30(11):2221-2231. https://doi.org/10.1038/leu.2016.107 PMid:27150009 PMCid:PMC5093052 |
||||
| 38. Wang Y, Zhu G, Wang J, Chen J. Irradiation alters the differentiation potential of bone marrow mesenchymal stem cells. Mol Med Rep. 2016; 13(1):213-223. https://doi.org/10.3892/mmr.2015.4539 PMid:26572960 PMCid:PMC4686093 |
||||
| 39. Kawase T, Okuda K, Nagata M, et al. Non-invasive, quantitative assessment of the morphology of γ-irradiated human mesenchymal stem cells and periosteal cells using digital holographic microscopy. Int J Radiat Biol. 2016; 92(12):796-805. https://doi.org/10.1080/09553002.2016.1230242 PMid:27586164 |
||||
| 40. Rühle A, Xia O, Perez RL, et al. The Radiation Resistance of Human Multipotent Mesenchymal Stromal cells Is Independent of Their Tissue of Origin. Int J Radiat Oncol Biol Phys. 2018; 100(5):1259-1269. https://doi.org/10.1016/j.ijrobp.2018.01.015 PMid:29452769 |
||||
| 41. Friedenstein AI, Luria EA. Kletochnye osnovy krovetvornogo mikrookruzheniya [Cellular basis of hematopoietic microenvironment]. Moscow: Medicine, 1980. 216 p. [In Russian] PMid:7021339 | ||||
| 43. Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies. Front Immunol. 2017; 8:339. https://doi.org/10.3389/fimmu.2017.00339 PMid:28424688 PMCid:PMC5371613 |
||||
| 44. Keane C, Jerkic M, Laffey JG. Stem Cell-based Therapies for Sepsis. Anesthesiology. 2017; 127(6):1017-1034. https://doi.org/10.1097/ALN.0000000000001882 PMid:28872482 |
||||
| 45. Pachler K, Ketterl N, Desgeorges A, et al. An In Vitro Potency Assay for Monitoring the Immunomodulatory Potential of Stromal Cell-Derived Extracellular Vesicles. Int J Mol Sci. 2017; 18(7):1413. https://doi.org/10.3390/ijms18071413 PMid:28671586 PMCid:PMC5535905 |
||||
| 46. Cheung TS, Dazzi F. Mesenchymal-myeloid interaction in the regulation of immunity. Semin Immunol. 2018; 35:59-68. https://doi.org/10.1016/j.smim.2018.01.002 PMid:29395680 |
||||
| 47. Mousa HSE, Shalaby SM, Gouda ZA, et al. Efficacy of human umbilical cord derived-mesenchymal stem cells in treatment of rat bone marrow exposed to gamma irradiation. Ann Anat. 2017; 210:64-75. https://doi.org/10.1016/j.aanat.2016.12.002 PMid:27987402 |
||||
| 48. Shim S, Lee SB, Lee JG, et al. Mitigating effects of hUCB-MSCs on the hematopoietic syndrome resulting from total body irradiation. Exp Hematol. 2013; 41(4):346-353. https://doi.org/10.1016/j.exphem.2013.01.002 PMid:23333483 |
||||
Nikolska K. The effects of the transplantation of thymus-derived multipotent stromal cells on the immune system and survival of lethally irradiated mice. Cell and Organ Transplantology. 2018; 6(2):158-163. doi:10.22494/cot.v6i2.88
