scbmtБИОМЕДИЦИНАJournal Biomed2074-59822713-0428Scientific center of biomedical technologies of Federal Medical and Biological Agencyscbmt-64Research ArticleМЕТОДЫ БИОМЕДИЦИНСКИХ ИССЛЕДОВАНИЙMETHODS OF BIOMEDICAL RESEARCHESПерспективы клинического применения мультипотентных мезенхимных стромальных клеток для регенерации хрящевой гиалиновой тканиProspects of clinical application of multipotent mesenchymal stromal cells for regeneration of hyaline cartilaginous tissueКоржиковаС. В.KorzhikovaS. V.sv_vasil@mail.ruФроловЕ. В.FrolovE. V.noemail@neicon.ruТепляшинЗ. А.TeplyashinZ. A.noemail@neicon.ruВоловенкоВ. Н.VolovenkoV. N.noemail@neicon.ruТепляшинА. С.TeplyashinA. S.noemail@neicon.ruЦентр клеточных технологий ООО «Бьюти Плаза»Russian FederationФГБОУ ВО «Ярославский государственный медицинский Университет» Минздрава РоссииRussian Federation201726022019022332Copyright © Коржикова С.В., Фролов Е.В., Тепляшин З.А., Воловенко В.Н., Тепляшин А.С., 20192019Коржикова С.В., Фролов Е.В., Тепляшин З.А., Воловенко В.Н., Тепляшин А.С.Korzhikova S.V., Frolov E.V., Teplyashin Z.A., Volovenko V.N., Teplyashin A.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.scbmt.ru/jour/article/view/64

Разработан биотрансплантат для внутрисуставного введения на основе мультипотентных мезенхимных стромальных клеток (ММСК) жировой ткани (ЖТ) и гелевого носителя, способствующий регенерации хрящевой гиалиновой ткани. Выбор клеток основан на способности ММСК ЖТ дифференцироваться в клетки хрящевой ткани (хондробласты и хондроциты) при индукции к хондродифференцировке. Подобран оптимальный носитель для доставки клеток в область дефекта, по консистенции аналогичный синовиальной жидкости, поддерживающий жизнеспособность, пролиферативную активность и хондрогенные потенции ММСК внутри сустава. Продемонстрировано, что при внутрисуставном введении кроликам биотрансплантата, состоящего из аутологичных ММСК ЖТ и гелевого носителя на основе производных целлюлозы, происходит полноценная регенерация дефекта хрящевой гиалиновой ткани.

Developed biotransplant for intra-articular introduction multipotent mesenchymal stromal cells (MMSC) adipose tissue (AT) and gel media to promote regeneration of hyaline cartilage tissue. Selection of cells based on the ability of MMSCs to differentiate into adipose cartilage cells (chondroblasts and chondrocytes) for induction to chondrodysplastic. Optimal carrier to deliver the cells in the defect, the consistency is similar to synovial fluid, supporting the viability, proliferative activity and chondrogenic potential of MSC inside the joint. It is demonstrated that with intra-articular introduction of rabbits biotransplant consisting of autologous MMSC AT and gel media on the basis of derivatives of cellulose is a complete regeneration of the defect with hyaline cartilaginous tissue.

биотрансплантатгиалиновый хрящдефект суставного хрящадифференцировкакроликимультипотентные мезенхимные стромальные клеткиbiological transplanthyaline cartilagejoint cartilage defectdifferentiationrabbitsmultipotent mesenchymal stromal cellsReferencesВербицкий Д.А., Жуковский В.А., Немилов В.Е., Слепцов И.В., Жуковская И.И. Способ получения геля на основе карбоксиметилцеллюлозы. 2007. Патент РФ № 2352584.Вербицкий Д.А., Жуковский В.А., Немилов В.Е., Слепцов И.В., Жуковская И.И. Способ получения геля на основе карбоксиметилцеллюлозы. 2007. Патент РФ № 2352584.Тепляшин А.С., Коржикова С.В., Шарифуллина С.З., Ростовская М.С., Чупикова Н.И., Васюнина Н.Ю., Андронова Н.В., Трещалина Е.М., Савченкова И.П. Дифференцировка мезенхимных стволовых клеток костного мозга человека в клетки хрящевой ткани при культивировании их в трехмерных матриксах OPLA in vitro // Цитология. 2007. № 49 (7). С. 544-51.Тепляшин А.С., Коржикова С.В., Шарифуллина С.З., Ростовская М.С., Чупикова Н.И., Васюнина Н.Ю., Андронова Н.В., Трещалина Е.М., Савченкова И.П. Дифференцировка мезенхимных стволовых клеток костного мозга человека в клетки хрящевой ткани при культивировании их в трехмерных матриксах OPLA in vitro // Цитология. 2007. № 49 (7). С. 544-51.Тепляшин А.С., Чупикова Н.И., Коржикова С.В., Шарифуллина С.З., Ростовская М.С., Савченкова И.П. Сравнительный анализ двух клеточных популяций с фенотипом, подобным мезенхимным стволовым клеткам, выделенных из разных участков подкожно-жировой клетчатки // Цитология. 2005. № 47(7). С. 637-643.Тепляшин А.С., Чупикова Н.И., Коржикова С.В., Шарифуллина С.З., Ростовская М.С., Савченкова И.П. Сравнительный анализ двух клеточных популяций с фенотипом, подобным мезенхимным стволовым клеткам, выделенных из разных участков подкожно-жировой клетчатки // Цитология. 2005. № 47(7). С. 637-643.Chen F.H., Rousche K.T., Tuan R.S. Technology Insight: adult stem cells in cartilage regeneration and tissue engineering // Nat. clin. pract. rheumatol. 2006. No. 2. Pp. 373-382.Chen F.H., Rousche K.T., Tuan R.S. Technology Insight: adult stem cells in cartilage regeneration and tissue engineering // Nat. clin. pract. rheumatol. 2006. No. 2. Pp. 373-382.Farr J., Cole B., Dhawan A., et. al. Clinical cartilage restoration: evolution and overview // Clin. Orthop. Relat. Res. 2011. No. 469. Pp. 2696-2705.Farr J., Cole B., Dhawan A., et. al. Clinical cartilage restoration: evolution and overview // Clin. Orthop. Relat. Res. 2011. No. 469. Pp. 2696-2705.Fridenshtein A.J., Deriglazova U.F., Kulagina N.N., et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method // Exp. Hematol. 1974. No. 2. Pp. 83-92.Fridenshtein A.J., Deriglazova U.F., Kulagina N.N., et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method // Exp. Hematol. 1974. No. 2. Pp. 83-92.Kobayashi T., Ochi M., Yanada S., Ishikawa M., Adachi N., Deie M., Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair // Arthroscopy. 2008. No. 24(6). Pp. 9-76.Kobayashi T., Ochi M., Yanada S., Ishikawa M., Adachi N., Deie M., Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair // Arthroscopy. 2008. No. 24(6). Pp. 9-76.Niemeyer P., Lenz P., Kreuz P.C., Salzmann G.M., Sьdkamp N.P., Schmal H., Steinwachs M. Chondrocyte-seededtype I/III collagen membrane for autologous chondrocyte transplantation: prospective 2-year results in patients with cartilage defects of the knee joint // Arthroscopy. 2010. No. 26. Pp. 1074-1082.Niemeyer P., Lenz P., Kreuz P.C., Salzmann G.M., Sьdkamp N.P., Schmal H., Steinwachs M. Chondrocyte-seededtype I/III collagen membrane for autologous chondrocyte transplantation: prospective 2-year results in patients with cartilage defects of the knee joint // Arthroscopy. 2010. No. 26. Pp. 1074-1082.Poncelet A.J., Denis D., Gianello P. Cellular xenotransplantation // Curr. opin. organ. transplant. 2009. No. 14. Pp. 168-174.Poncelet A.J., Denis D., Gianello P. Cellular xenotransplantation // Curr. opin. organ. transplant. 2009. No. 14. Pp. 168-174.Shapiro F., Kolde S., Glimsher M. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage // J. Bone. Joint Surg. 1993. No. 75. Pp. 532-553.Shapiro F., Kolde S., Glimsher M. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage // J. Bone. Joint Surg. 1993. No. 75. Pp. 532-553.Steinwachs M.R., Kreuz P.C. Clinical results of autologous chondroxyte transplantation (ACT) using a collagen membrane. In: Сartilage surgery and future perspectives. - Springer Berlin, Heidelberg, New York. 2003. Pp. 37-48.Steinwachs M.R., Kreuz P.C. Clinical results of autologous chondroxyte transplantation (ACT) using a collagen membrane. In: Сartilage surgery and future perspectives. - Springer Berlin, Heidelberg, New York. 2003. Pp. 37-48.Teplyashin A.S., Korjikova S.V., Sharifullina S.Z., Chupikova N.I., Rostovskaya M.S., Vasyunina N.Y., Savtchenkova I.P. Engineering cartilage-like tissue using adipose-derived adult stem cells and collagen scaffolds // Tissue Engineering. 2006. No. 12. P. 1117.Teplyashin A.S., Korjikova S.V., Sharifullina S.Z., Chupikova N.I., Rostovskaya M.S., Vasyunina N.Y., Savtchenkova I.P. Engineering cartilage-like tissue using adipose-derived adult stem cells and collagen scaffolds // Tissue Engineering. 2006. No. 12. P. 1117.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. United States Patent No. 7,915,039 B2.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. United States Patent No. 7,915,039 B2.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. European patent No. 1 733 027 B1.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. European patent No. 1 733 027 B1.Wakitani S., Imoto K., Yamomoto T., et al. Human autologous culture expanded bone marrow mesenchimal cell transplantation for repair of cartilage defects in osteoarthritic knees // Osteoarthritis cartilage. 2002. No. 10. Pp. 199-206.Wakitani S., Imoto K., Yamomoto T., et al. Human autologous culture expanded bone marrow mesenchimal cell transplantation for repair of cartilage defects in osteoarthritic knees // Osteoarthritis cartilage. 2002. No. 10. Pp. 199-206.Zeile G. Intracytoplasmic immunofluorescence in multiple myeloma // Cytometry. 1980. No. 1. Pp. 37-41.Zeile G. Intracytoplasmic immunofluorescence in multiple myeloma // Cytometry. 1980. No. 1. Pp. 37-41.Zuk P.A., Zhu M., Ashjian P., de Ugarte D.D., Huang J.I., Mizuno H., Alfonso Z.C., Fraiser J.K., Benhaim P., Hedrik M.H. Human adipose tissue is sourse of multipotent stem cells // Mol. biol. cell. 2002. No. 13. Pp. 4279-4295.Zuk P.A., Zhu M., Ashjian P., de Ugarte D.D., Huang J.I., Mizuno H., Alfonso Z.C., Fraiser J.K., Benhaim P., Hedrik M.H. Human adipose tissue is sourse of multipotent stem cells // Mol. biol. cell. 2002. No. 13. Pp. 4279-4295.Zuk P.A., Zhu M., Mizuno H., Huang J.I., Futrell W.J., Katz A.J., Benhaim P., Lorenz H.P., Hedrik M.H. Multilineage cells from human adipose tissue: implications for cell-based therapies // Tissue Eng. 2001. No. 7. Pp. 211-226.Zuk P.A., Zhu M., Mizuno H., Huang J.I., Futrell W.J., Katz A.J., Benhaim P., Lorenz H.P., Hedrik M.H. Multilineage cells from human adipose tissue: implications for cell-based therapies // Tissue Eng. 2001. No. 7. Pp. 211-226.Verbickij D.A., Zhukovskij V.A., Nemilov V.E., Slepcov I.V., Zhukovskaja I.I. Sposob poluchenija gelja na osnove karboksimetilcelljulozy. 2007. Patent RF № 2352584.Verbickij D.A., Zhukovskij V.A., Nemilov V.E., Slepcov I.V., Zhukovskaja I.I. Sposob poluchenija gelja na osnove karboksimetilcelljulozy. 2007. Patent RF № 2352584.Tepljashin A.S., Korzhikova S.V., Sharifullina S.Z., Rostovskaja M.S., Chupikova N.I., Vasjunina N.Ju., Andronova N.V., Treshhalina E.M., Savchenkova I.P. Differencirovka mezenhimnyh stvolovyh kletok kostnogo mozga cheloveka v kletki hrjashhevoj tkani pri kul'tivirovanii ih v trehmernyh matriksah OPLA in vitro // Citologija. 2007. № 49 (7). S. 544-51.Tepljashin A.S., Korzhikova S.V., Sharifullina S.Z., Rostovskaja M.S., Chupikova N.I., Vasjunina N.Ju., Andronova N.V., Treshhalina E.M., Savchenkova I.P. Differencirovka mezenhimnyh stvolovyh kletok kostnogo mozga cheloveka v kletki hrjashhevoj tkani pri kul'tivirovanii ih v trehmernyh matriksah OPLA in vitro // Citologija. 2007. № 49 (7). S. 544-51.Tepljashin A.S., Chupikova N.I., Korzhikova S.V., Sharifullina S.Z., Rostovskaja M.S., Savchenkova I.P. Sravnitel'nyj analiz dvuh kletochnyh populjacij s fenotipom, podobnym mezenhimnym stvolovym kletkam, vydelennyh iz raznyh uchastkov podkozhno-zhirovoj kletchatki // Citologija. 2005. № 47(7). S. 637-643.Tepljashin A.S., Chupikova N.I., Korzhikova S.V., Sharifullina S.Z., Rostovskaja M.S., Savchenkova I.P. Sravnitel'nyj analiz dvuh kletochnyh populjacij s fenotipom, podobnym mezenhimnym stvolovym kletkam, vydelennyh iz raznyh uchastkov podkozhno-zhirovoj kletchatki // Citologija. 2005. № 47(7). S. 637-643.Chen F.H., Rousche K.T., Tuan R.S. Technology Insight: adult stem cells in cartilage regeneration and tissue engineering // Nat. clin. pract. rheumatol. 2006. No. 2. Pp. 373-382.Chen F.H., Rousche K.T., Tuan R.S. Technology Insight: adult stem cells in cartilage regeneration and tissue engineering // Nat. clin. pract. rheumatol. 2006. No. 2. Pp. 373-382.Farr J., Cole B., Dhawan A., et. al. Clinical cartilage restoration: evolution and overview // Clin. Orthop. Relat. Res. 2011. No. 469. Pp. 2696-2705.Farr J., Cole B., Dhawan A., et. al. Clinical cartilage restoration: evolution and overview // Clin. Orthop. Relat. Res. 2011. No. 469. Pp. 2696-2705.Fridenshtein A.J., Deriglazova U.F., Kulagina N.N., et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method // Exp. Hematol. 1974. No. 2. Pp. 83-92.Fridenshtein A.J., Deriglazova U.F., Kulagina N.N., et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method // Exp. Hematol. 1974. No. 2. Pp. 83-92.Kobayashi T., Ochi M., Yanada S., Ishikawa M., Adachi N., Deie M., Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair // Arthroscopy. 2008. No. 24(6). Pp. 9-76.Kobayashi T., Ochi M., Yanada S., Ishikawa M., Adachi N., Deie M., Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair // Arthroscopy. 2008. No. 24(6). Pp. 9-76.Niemeyer P., Lenz P., Kreuz P.C., Salzmann G.M., S'dkamp N.P., Schmal H., Steinwachs M. Chondrocyte-seededtype I/III collagen membrane for autologous chondrocyte transplantation: prospective 2-year results in patients with cartilage defects of the knee joint // Arthroscopy. 2010. No. 26. Pp. 1074-1082.Niemeyer P., Lenz P., Kreuz P.C., Salzmann G.M., S'dkamp N.P., Schmal H., Steinwachs M. Chondrocyte-seededtype I/III collagen membrane for autologous chondrocyte transplantation: prospective 2-year results in patients with cartilage defects of the knee joint // Arthroscopy. 2010. No. 26. Pp. 1074-1082.Poncelet A.J., Denis D., Gianello P. Cellular xenotransplantation // Curr. opin. organ. transplant. 2009. No. 14. Pp. 168-174.Poncelet A.J., Denis D., Gianello P. Cellular xenotransplantation // Curr. opin. organ. transplant. 2009. No. 14. Pp. 168-174.Shapiro F., Kolde S., Glimsher M. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage // J. Bone. Joint Surg. 1993. No. 75. Pp. 532-553.Shapiro F., Kolde S., Glimsher M. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage // J. Bone. Joint Surg. 1993. No. 75. Pp. 532-553.Steinwachs M.R., Kreuz P.C. Clinical results of autologous chondroxyte transplantation (ACT) using a collagen membrane. In: Sartilage surgery and future perspectives. - Springer Berlin, Heidelberg, New York. 2003. Pp. 37-48.Steinwachs M.R., Kreuz P.C. Clinical results of autologous chondroxyte transplantation (ACT) using a collagen membrane. In: Sartilage surgery and future perspectives. - Springer Berlin, Heidelberg, New York. 2003. Pp. 37-48.Teplyashin A.S., Korjikova S.V., Sharifullina S.Z., Chupikova N.I., Rostovskaya M.S., Vasyunina N.Y., Savtchenkova I.P. Engineering cartilage-like tissue using adipose-derived adult stem cells and collagen scaffolds // Tissue Engineering. 2006. No. 12. P. 1117.Teplyashin A.S., Korjikova S.V., Sharifullina S.Z., Chupikova N.I., Rostovskaya M.S., Vasyunina N.Y., Savtchenkova I.P. Engineering cartilage-like tissue using adipose-derived adult stem cells and collagen scaffolds // Tissue Engineering. 2006. No. 12. P. 1117.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. United States Patent No. 7,915,039 B2.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. United States Patent No. 7,915,039 B2.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. European patent No. 1 733 027 B1.Teplyashin A.S. Method for obtaining mesenchymal stem cells. 2011. European patent No. 1 733 027 B1.Wakitani S., Imoto K., Yamomoto T., et al. Human autologous culture expanded bone marrow mesenchimal cell transplantation for repair of cartilage defects in osteoarthritic knees // Osteoarthritis cartilage. 2002. No. 10. Pp. 199-206.Wakitani S., Imoto K., Yamomoto T., et al. Human autologous culture expanded bone marrow mesenchimal cell transplantation for repair of cartilage defects in osteoarthritic knees // Osteoarthritis cartilage. 2002. No. 10. Pp. 199-206.Zeile G. Intracytoplasmic immunofluorescence in multiple myeloma // Cytometry. 1980. No. 1. Pp. 37-41.Zeile G. Intracytoplasmic immunofluorescence in multiple myeloma // Cytometry. 1980. No. 1. Pp. 37-41.Zuk P.A., Zhu M., Ashjian P., de Ugarte D.D., Huang J.I., Mizuno H., Alfonso Z.C., Fraiser J.K., Benhaim P., Hedrik M.H. Human adipose tissue is sourse of multipotent stem cells // Mol. biol. cell. 2002. No. 13. Pp. 4279-4295.Zuk P.A., Zhu M., Ashjian P., de Ugarte D.D., Huang J.I., Mizuno H., Alfonso Z.C., Fraiser J.K., Benhaim P., Hedrik M.H. Human adipose tissue is sourse of multipotent stem cells // Mol. biol. cell. 2002. No. 13. Pp. 4279-4295.Zuk P.A., Zhu M., Mizuno H., Huang J.I., Futrell W.J., Katz A.J., Benhaim P., Lorenz H.P., Hedrik M.H. Multilineage cells from human adipose tissue: implications for cell-based therapies // Tissue Eng. 2001. No. 7. Pp. 211-226.Zuk P.A., Zhu M., Mizuno H., Huang J.I., Futrell W.J., Katz A.J., Benhaim P., Lorenz H.P., Hedrik M.H. Multilineage cells from human adipose tissue: implications for cell-based therapies // Tissue Eng. 2001. No. 7. Pp. 211-226.

The authors declare that there are no conflicts of interest present.