Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute217695ReviewsНаучные обзорыReview ArticlePossible pathways of regener ative strategy in correction of type I diabetes mellitus by methods of cell transplantationВозможные пути реализации регенерационной стратегии при лечении сахарного диабета I типа методами клеточной трансплантацииZakiryanovA. R.ЗакирьяновА. Р.
Russian Federation

The stem cell biotechnology laboratory

Лаборатория биотехнологии стволовых клеток

logart@mail.ruOnishchenkoN. A.ОнищенкоН. А.
Russian Federation

The stem cell biotechnology laboratory

Лаборатория биотехнологии стволовых клеток

logart@mail.ruResearch institute of transplantology and artificial organsФГУ НИИ Трансплантологии и искусственных органов Росздрава150620072223331002202310022023Copyright ©; 2023, Eco-VectorCopyright ©; 2023, Эко-Вектор2023Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/217695

This review describes up to date concepts of pancreatic b-cell and islets of Langerhans physiological and reparative regeneration during type I diabetes mellitus. Modern approaches to recovery of lacking b-cell population with transplantation of allogenic islet cells, in vitro differentiated adult pancreatic progenitors or embryonic stem cells are considered. Possible pathways of in vivo tissue regeneration induction or immune correction in type I diabetes mellitus with bone marrow and cord blood stem cell therapy are analyzed.

В обзоре представлены современные концепции физиологической и репаративной регенерации b-клеток и островков Лангерганса поджелудочной железы при сахарном диабете I типа. Рассмотрены современные подходы к восполнению пула утраченных b-клеток за счет аллогенной трансплантации островковых клеток, а также in vitro дифференцировки взрослых прогениторных клеток поджелудочной железы и эмбриональных стволовых клеток; проанализированы возможные пути индукции in vivo тканеспецифичной регенерации и устранения дизрегуляции иммунной системы при сахарном диабете I типа с помощью терапии стволовыми клетками костного мозга и пуповинной крови.

type I diabetes mellitusregeneration cell therapyβ-cellislets of Langerhansreplicationneogenesisstem cellsсахарный диабет I типарегенерационная клеточная терапияβ-клеткиостровки Лангергансарепликациянеогенезстволовые клеткиДедов И.И., Никонова Т.В., Смирнова О.В. и др. Роль цитокинов в регуляции иммунного ответа и механизмы гибели в-клеток при различных вариантах течения сахарного диабета I типа. Вопросы эндокринологии 2005; 51(3): 3-7.Балаболкин М.И. Диабетология. М.: Медицина; 2000.Ефимов А.С. Диабетические ангиопатии. М.: Медицина; 1989.Rabinovitch А, Suarez-Pinzon W.L. Role of cytokines in the pathogenesis of autoimmune diabetes mellitus. Rev. Еndocr. Metab. Disord. 2003; 4(3): 291-99.Делягин В.М., Волков И.Э., Румянцев А.Г., Скуркович С.В. Иммунные и неиммунные нарушения при сахарном диабете типа 1 у детей. Вопросы гематологии / онкологии и иммунопатологии в педиатрии 2004; 3(2): 76-80.Prud’homme G.J., Piccirillo С.А. The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J. Аutoimmun. 2000; 14(1): 23-42.Peterson J.D., Pike B., Dallas-Pedretti А. et al. Induction of diabetes with islet-specific T-cell clones in age dependent. Immunology 1995; 85(3): 455-60.Winter W.Е., Harris N., Schatz D. Immunological marker in the diagnosis and prediction of autoimmune type 1a diabetes. Сlin. Diabetes 2002; 20: 183-91.Колесник Ю.М., Орловский М.А. Панкреатические островки: некоторые аспекты морфологии, физиологии и процессов деструкции при сахарном диабете 1 типа. Проблемы эндокринологии 2004; 50(2): 3-10.Yoon J.W., Jun H.S. Аutoimmune destruction of pancreatic beta cells. Аm. J. Ther. 2005; 12(6): 580-91.Бабаева А.Г. Роль иммунной системы в дизрегуляции морфогенетических процессов. В кн.: Крыжановский Г.Н., редактор. Дизрегуляционная патология. М.: Медицина; 2002: 366-85.Бабаева А.Г. Иммунологические реакции в процессах нормального и восстановительного роста. В кн.: Регенерация и клеточное деление. М.: Медицина; 1968: 11-6.Бабаева А.Г. О роли гуморальных и клеточных факторов иммунитета в регуляции процессов восстановления внутренних органов позвоночных. В кн.: Лиознер Л.Д., Доброхотов В.Н., редакторы. Восстановительные и пролиферативные процессы у животных. М.: Наука; 1968: 66-82.Бабаева А.Г. Регенерация и система иммуногенеза. М.: Медицина; 1985.Бабаева А.Г. Прошлое, настоящее и будущее проблемы лимфоидной регуляции пролиферации нелимфоидных клеток. БЭБМ 1995; 9: 230-34.Бабаева А.Г., Зотиков Е.А. Иммунология процессов адаптивного роста, пролиферации и их нарушений. М.: Наука; 1987.Бабаева А.Г. Единство и противоположность цитогенетической активности лимфоцитов и их антителообразующей функции при восстановительных процессах в органах. БЭБМ 1999; 11: 484-90.Bonner-Weir S. Beta-cell turnover: its assesment and implications. Diabetes 2001; 50 Suppl 1: S20-S24.Bouwens L., Rooman I. Regulation of pancreatic beta-cell mass. Physiol. Rev. 2005; 85(4): 1255-70.Herold K.С., Аblamunits V., Sherry N.А. et al. Аutoimmunity and beta cell regeneration in mouse and human type 1 diabetes: The peace is not enough. Аnn. N. Y. Аcad. Sci. 2007; in press.Scholin A., Torn C., Nystrom L. et al. Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in type 1 diabetes. Diabet. Med. 2004; 21(5): 447-55.Chase H.P., MacKenzie T.A., Burdick J. et al. Redefining the clinical remission period in children with type 1 diabetes. Pediatr. Diabetes 2004; 5(1): 16-9.Karges B., Durinovic-Bello I., Heinze E. et al. Immunological mechanisms associated with long-term remission of human type 1 diabetes. Diabetes Metab. Res. Rev. 2006; 22(3): 184-9.Ortqvist E., Falorni A., Scheynius A. et al. Age governs gender-dependent islet cell autoreactivity and predicts the clinical course in childhood IDDM. Acta Paediatr. 1997; 86 (11): 1166-71.Muhammad B.J., Swift P.G., Raymond N.T. et al. Partial remission phase of diabetes in children younger than age 10 years. Arch. Dis. Child. 1999; 80(4): 367-9.Scholin A., Berne C., SchvarczE. et al. Factors predicting clinical remission in adult patients with type 1 diabetes. J. Intern. Med. 1999; 245(2): 155-62.Gepts W. Pathological anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965; 14(10): 619-33.Meier J.J., Lin J.C., Butler A.E. et al. Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia. 2006; 49(8): 1838-44.Karges B., Durinovic-Bello I., Heinze E. et al. Complete long-term recovery of beta-cell function in autoimmune type 1 diabetes after insulin treatment. Diabetes Care. 2004; 27(5): 1207-08.Bonfanti R., Bognetti E., Meschi F. et al. Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty. Acta Diabetol. 1998; 35(2): 91-5.Peshavaria M., Larmie B.L., Lausier J. et al. Regulation of pancreatic beta-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse. Diabetes 2006; 55(12): 3289-98.Peters K., Panienka R., Li J. et al. Expression of stem cell markers and transcription factors during the remodeling of the rat pancreas after duct ligation. Virchows Arch. 2005; 446(1): 56-63.Tiemann K., Panienka R., Kloppel G. Expression of transcription factors and precursor cell markers during regeneration of beta cells in pancreata of rats treated with streptozotocin. Virchows Arch. 2007; 450(3): 261-66.De Haro-Hernandez R., Cabrera-Munoz L., Mendez J.D. Regeneration of beta-cells and neogenesis from small ducts or acinar cells promote recovery of endocrine pancreatic function in alloxan-treated rats. Arch. Med. Res. 2004; 35(2):114-20.Lipsett M., Finegood D.T. Вeta-cell neogenesis during prolonged hyperglycemia in rats. Diabetes. 2002; 51(6): 1834-1841.Gu D., Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-г transgenic mice. Development 1993; 118(1): 33-46.Campbell I.L., Hobbs M.V., Dockter J. et al. Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin- 6 in transgenic mice. Am. J. Pathol. 1994; 145(1): 157-66.Yamada S., Kojima I. Regenerative medicine of the pancreatic в cells. J. Hepatobiliary Pancreat. Surg. 2005; 12(3): 218-26.Banerjee M.,Kanitkar M.,Bhonde P.R. Approaches towards endogenous pancreatic regeneration. Rev. Diabet. Stud. 2005; 2(3): 165-76.Duvillie B., Currie C., Chrones T. et al. Increased islet cell proliferation, decreased apoptosis and greater vascularization leading to в-cell hyperplasia in mutant mice lacking insulin. Endocrinology 2002; 143(4): 1530-7.Georgia S., Bhushan A. Beta-cell replication is the primary mechanism for maintaining postnatal beta-cell mass. J. Clin. Invest. 2004; 114(7): 963-8.Dor Y., Brown J., Martinez O.I. et al. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429(6987): 41-6.Bonner-Weir S., Sharma A. Are there pancreatic progenitor cells from which new islets form after birth? Nat. Clin. Prac. Endocrinol. Metab. 2006; 2(5): 240-1.Bonner-Weir S., Toschi E., Inada A. et al. The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr. Diabetes 2004; 5 Suppl 2:16-22.Butler A.E., Janson J., Bonner-Weir S. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52(1): 102-10.Tyrberg B., Ustinov J., Otonkoski T. et al. Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets: effects of the ob gene and compensatory growth of the implantation organ. Diabetes 2001; 50(2): 301-7.Meier J.J., Bhushan A., Butler A.E. et al. Sustained beta-cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 2005; 48: 2221-8.Rosenberg L., Lipsett M., Yoon J.W. et al. A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Ann. Surg. 2004; 240(5): 875-84.Brubaker P.L., Drucker D.J. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004; 145(6): 2653-59.Li L., Yi Z., Seno M. et al. Activin A and betacellulin: effect on regeneration of pancreatic beta-cells in neonatal streptozotocin-treated rats. Diabetes 2004; 53(3): 608-15.Rooman I., Bouwens L. Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57BI6/ J mice treated with alloxan. Diabetologia 2004; 47(2): 259-65.Suarez-Pinzon W.L., Lakey J.R., Brand S.J. et al. Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. J. Clin. Endocrinol. Metab. 2005; 90(6): 3401-9.Ratner R.E., Feeley D., Buse J.B. et al. Double-blind, placebo-controlled trial of islet neogenesis gene associated protein (INGAP) in type 1 diabetes. Diabetes 2005; 54 Suppl 1:11-LB (late breaking abstract).Beattie G.M., Montgomery A.M., Lopez A.D. et al. A novel approach to increase human islet cell mass while preserving beta-cell function. Diabetes 2002; 51(12): 3435-39.Lingohr M.K., Dickson L.M., McCuaig J.F. et al. Activation of IRS-2- mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. Diabetes 2002; 51(4): 966-76.Huotari M.A., Palgi J., Otonkoski T. Growth factor-mediated proliferation and differentiation of insulin-producing INS-1 and RINm5F cells: identification of betacellulin as a novel beta-cell mitogen. Endocrinology 1998; 139(4): 1494-99.Ritzel R.A., Butler P.C. Replication increases beta-cell vulnerability to human islet amyloid polypeptide-induced apoptosis. Diabetes 2003; 52(7): 1701-8.Meier J.J., Ritzel R.A., Maedler K. et al. Increased vulnerability of newly forming beta-cells to cytokine-induced cell death. Diabetologia 2006; 49(1): 83-9.Atkinson M.A., Rhodes C.J. Pancreatic regeneration in type 1 diabetes: dreams on a deserted islet? Diabetologia 2005; 48(11): 2200-2.Yang Z., Chen M., Carter J.D. et al. Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes. Biochem. Biophys. Res. Commun. 2006; 344(3): 1017-22.Kodama S., Kuhtreiber W., Fujimura S. et al. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302(5648): 1223-7.Suri A., Calderon B., Esparza T.J. et al. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006; 311(5768): 1778-80.Nishio J., Gaglia J.L., Turvey S.E. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006; 311(5768): 1775-8.Chong A.S., Shen J., Tao J. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311(5768): 1774-5.Melton D.A. Reversal of type 1 diabetes in mice. N. Engl. J. Med. 2006; 355 (1): 89-90.Bretzel R., Brendel M., Hering B. International Islet Transplant Registry, Newsletter №9. 2001; 8:1.Bretzel R., Brendel M., Hering B. International Islet Transplantat Registry, Newsletter №8. 1999.Shapiro A.M., Lakey J.R., Ryan E.A. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 2000; 343(4): 230-8.Hirshberg B., Rother K.I., Digon B.J. 3rd. et al. Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care. 2003; 26(12): 3288-95.Shapiro A.M., Lakey J.R., Paty B.W. et al. Strategic opportunities in clinical islet transplantation. Transplantation. 2005; 79(10): 1304-7.Ryan E.A., Paty B.W., Senior P.A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54(7): 2060-9.Скалецкий H.H. Трансплантация островковых клеток в лечении сахарного диабета: современное состояние и перспективы. Вестник транспл. и искусствен. органов 2005; 3:17-18.Maffi P., Angeli E., Bertuzzi F. et al. Minimal focal steatosis of liver after islet transplantation in humans: a long-term study. Cell. Transplant. 2005; 14(10): 727-733.Street C.N., Lakey J.R., Shapiro A.M. et al. Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome. Diabetes 2004; 53(12): 3107-14.Narang A.S., Mahato R.I. Biological and biomaterial approaches for improved islet transplantation. Pharmacol. Rev. 2006; 58(2): 194-243.Шумаков В.И., Скалецкий H.H. Регуляция углеводного обмена и коррекция его нарушений при сахарном диабете. В кн.: Шумаков В.И., редактор. Очерки по физиологическим проблемам трансплантологии и искусственных органов. Тула: Репроникс Лтд; 1998.Блюмкин В.Н., Скалецкий H.H., Кирсанова Л.А. и др. Борьба с осложнениями сахарного диабета как основная цель трансплантации островковых клеток поджелудочной железы. Гипотезы, объясняющие лечебный эффект трансплантации. Транспл. и искусствен. органы 1998; 4: 65.Скалецкий H.H., Онищенко H.A. Клеточная трансплантация: достижения и перспективы. Вестник транспл. и искусствен. органов 2001; 3-4: 94-102.Levy M.F. Animal organs for human transplantation: how close are we? Proc. (Bayl. Univ. Med. Cent.). 2000; 13(1): 3-6.Dvash T., Benvenisty N. Human embryonic stem cells as a model for early human development. Best Pract. Res. Clin. Obstet. Gynaecol. 2004; 18(6): 929-40.Soria B., Roche E., Berna G. et al. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes. 2000; 49(2): 157-62.Assady S., Maor G., Amit M. et al. Insulin production by human embryonic stem cells. Diabetes. 2001; 50(8): 1691-7.Lumelsky N., Blondel O., Laeng P. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001; 292(5520): 1389-94.Hori Y., Rulifson I.C., Tsai B.C. et al. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc. Natl. Acad. Sci. USA 2002; 99(25): 16105-110.Kahan B.W., Jacobson L.M., Hullett D.A. et al. Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation. Diabetes 2003; 52(8): 2016-24.Segev H., Fishman B., Ziskind A. et al. Differentiation of human embryonic stem cells into insulin-producing clusters. Stem Cells 2004; 22(3): 265-74.Blyszczuk P., Czyz J., Kania G. et al. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc. Natl. Acad. Sci. USA 2003; 100(3): 998-1003.Blyszczuk P., Asbrand C., Rozzo A. et al. Embryonic stem cells differentiate into insulin-producing cells without selection of nestin-expressing cells. Int. J. Dev. Biol. 2004; 48(10): 1095-104.Miyazaki S., Yamato E., Miyazaki J. Regulated expression of Pdx1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 2004; 53(4): 1030-37.Leon-Quinto T., Jones J., Skoudy A. et al. In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 2004; 47(8): 1442-51.Lee S.H., Lumelsky N., Studer L. et al. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat. Biotechnol. 2000; 18(6): 675-9.Rajagopal J., Anderson W.J., Kume S. et al. Insulin staining of ES cell progeny from insulin uptake. Science 2003; 299(5605): 363.Hansson M., Tonning A., Frandsen U. et al. Artifactual insulin release from differentiated embryonic stem cells. Diabetes 2004; 53(10): 2603-9.Hori Y., Gu X., Xie X. et al. Differentiation of insulin-producing cells from human neural progenitor cells. PLoS Med. 2005; 2(4): e103.Kubo A., Shinozaki K., Shannon J.M. et al. Development of definitive endoderm from embryonic stem cells in culture. Development 2004; 131(7): 1651-62.Ku H.T., Zhang N., Kubo A. et al. Committing embryonic stem cells to early endocrine pancreas in vitro. Stem Cells 2004; 22(7): 1205-17.Ramiya V.K., Maraist M., Arfors K.E. et al. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat. Med. 2000; 6(3): 278-82.Bonner-Weir S., Taneja M., Weir G.C. et al. In vitro cultivation of human islets from expanded ductal tissue. Proc. Natl. Acad. Sci. USA 2000; 97(14): 7999- 8004.Gao R., Ustinov J., Pulkkinen M.A. et al. Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture. Diabetes 2003; 52(8): 2007-015.Rooman I., Lardon J., Bouwens L. Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes 2002; 51(3): 686-90.Heremans Y., Van De Casteele M., In't Veld P. et al. Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. J. Cell. Biol. 2002; 159(2): 303-12.Suzuki A., Nakauchi H., Taniguchi H. Prospective isolation of multipotent pancreatic progenitors using flow-cytometric cell sorting. Diabetes 2004; 53(8): 2143-52.Zulewski H., Abraham E.J., Gerlach M.J. et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 2001; 50(3): 521-33.Petropavlovskaya M., Rosenberg L. Identification and characterization of small cells in the adult pancreas: potential progenitor cells? Cell. Tissue Res. 2002; 310(1): 51-8.Seaberg R.M., Smukler S.R., Kieffer T.J. et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat. Biotechnol. 2004; 22(9): 1115-24.Piper K., Ball S.G., Turnpenny L.W. et al. Beta-cell differentiation during human development does not rely on nestin-positive precursors: implications for stem cell-derived replacement therapy. Diabetologia 2002; 45(7): 1045-47.Treutelaar M.K., Skidmore J.M., Dias-Leme C.L. et al. Nestin-lineage cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 2003; 52(10): 2503-12.Delacour A., Nepote V., Trumpp A. et al. Nestin expression in pancreatic exocrine cell lineages. Mech. Dev. 2004; 121(1): 3-14.Wang R.N., Kloppel G., Bouwens L. Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 1995; 38(12): 1405-11.Rooman I., Heremans Y.,Heimberg H. et al. Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro. Diabetologia 2000; 43(7): 907-14.Song K.H., Ko S.H., Ahn Y.B. et al. In vitro transdifferentiation of adult pancreatic acinar cells into insulin-expressing cells. Biochem. Biophys. Res. Commun. 2004; 316(4): 1094-100.Gershengorn М.С., Hardikar A.A., Wei C. et al. Epithelial-to- mesenchymal transition generates proliferative human islet precursor cells. Science 2004; 306(5705): 2261-4.Ianus A., Holz G.G., Theise N.D. et al. In vivo derivation of glucose- competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J. Clin. Invest. 2003; 111(6): 843-50.Taneera J., Rosengren A., Renstrom E. et al. Failure of transplanted bone marrow cells to adopt a pancreatic p-cell fate. Diabetes 2006; 55(2): 290-6.Choi J.B., Uchino H., Azuma K. et al. Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta cells. Diabetologia 2003; 46(10): 1366-74.Lechner A., Yang Y.G., Blacken R.A. et al. No evidence for significant transdifferentiation of bone marrow into pancreatic p-cells in vivo. Diabetes 2004; 53(3): 616-23.Jiang Y., Jahagirdar B.N., Reinhardt R.L. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418(6893): 41-9.Chen L.B., Jiang X.B., Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet betacells. World J. Gastroenterol. 2004; 10(20): 3016-20.Timper K., Seboek D., Eberhardt М. et al. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagons expressing cells. Biochem. Biophys. Res. Commun. 2006; 341(4): 1135-40.Moriscot C., De Fraipont F., Richard M.J. et al. Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 2005; 23(4): 594-604.Camargo F.D., Chambers S.M., Goodell M.A. Stem cell plasticity: from transdifferentiation to macrophage fusion. Cell prolif. 2004; 37(1): 55-65.Kinnaird T., Stabile E., Burnett M.S. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 2004; 94(5): 687-92.Izumida Y., Aoki T., Yasuda D. et al. Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta-cells. Biochem. Biophys. Res. Commun. 2005; 333(1): 273-82.Sonnenberg E., Meyer D., Weidner K.M. et al. Scatter factor/hepatocyte growth factor and its receptor, the c-Met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development, J. Cell Biol. 1993; 123(1): 223-35.Furukawa T., Duguid W.P., Kobari M. et al. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis, Am. J. Pathol. 1995; 147(4): 889-95.Otonkoski T., Cirulli V., Beattie M. et al. A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth, Endocrinology 1996; 137(7): 3131-9.Banerjee M., Kumar A., Bhonde R.R. Reversal of experimental diabetes by multiple bone marrow transplantation. Biochem. Biophys. Res. Commun. 2005; 328 (1): 318-25.Lee R.H., Seo M.J., Reger R.L. et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc. Natl. Acad. Sci. USA 2006; 103 (46): 17438-43.Hess D., Li L., Martin M. et al. Bone marrow-derived stem cells initiate pancreatic regeneration. Nat. Biotechnol. 2003; 21(7): 763-70.Loomans C.J., de Koning E.J., Staal F.J. et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 2004; 53(1): 195-9.Mathews V., Hanson P.T., Ford E. et al. Recruitment of bone marrow- derived endothelial cells to sites of pancreatic beta-cell injury. Diabetes 2004; 53(1):91-8.Lammert E., Cleaver O., Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science 2001; 294(5542): 564-7.Шахов Н.Л., Артамонов С.Д., Сускова B.C., Новикова В.К., Никольская А.О. Первый клинический опыт использования аутологичных гемопоэтических клеток для коррекции нарушений при сахарном диабете первого типа. Вестник транспл. и искусствен. органов 2005; 3: 48.Fernandez-Vha R., Saslavsky J., Andrin O. et al. Feasibility of implant autologous stem cells with endovascular technique in diabetes mellitus. Cytotherapy 2004; 7 Suppl: Abstract #37.Ende N., Chen R., Reddi A.S. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetes. Biochem. Biophys. Res. Commun. 2004; 325(3): 665-9.Couri C.E., Foss M.C., Voltarelli J.C. Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting p-cell regeneration. Braz. J. Med. Biol. Res. 2006; 39(10): 1271-1280.