• Трансплантация стволовых и прогениторных клеток в перспективе для коррекции последствий гипоксически-ишемической энцефалопатии у новорожденных

Трансплантация стволовых и прогениторных клеток в перспективе для коррекции последствий гипоксически-ишемической энцефалопатии у новорожденных

HEALTH OF WOMAN. 2016.10(116):110–120


Трансплантация стволовых и прогениторных клеток в перспективе для коррекции последствий гипоксически-ишемической энцефалопатии у новорожденных


Веропотвелян П. Н., Цехмистренко И. С., Веропотвелян Н. П., Гужевская И. В., Жабицкая Л. А., Журавлева С. А.

ОКУ «Межобластной центр медицинской генетики и пренатальной диагностики», г. Кривой Рог

Перинатальный центр, г. Киев

Национальный медицинский университет имени А.А. Богомольца, г. Киев


В данный обзор включены результаты исследований механизма терапевтического действия стволовых клеток при церебральных нарушениях у новорожденных.

В обзоре зарубежных публикаций проанализированы различные аспекты клеточной терапии, начиная от типа стволовых клеток и источников их получения. Изучены компоненты, определяющие положительный эффект применительно к терапии гипоксий/ишемий головного мозга.

Показана высокая терапевтическая эффективность клеточных технологий и перспективность их применения в неонатологии. Однако необходимо дальнейшее изучение данной проблемы, направленное на определение всесторонней характеристики типа клеток и их доз, оптимального времени и метода их введения, для наиболее эффективного применения клеточной терапии.


Ключевые слова: стволовые клетки, новорожденные, гипоксически-ишемическая энцефалопатия, асфиксия.


Литература: 
1. Ali J.M. Allorecognition pathways in transplant rejection and tolerance / J.M. Ali, E.M. Bolton, J.A. Bradley, G.J. Pettigrew // Transplantation. 2013; 96(8): 681-8. https://doi.org/10.1097/TP.0b013e31829853ce; PMid:23715047

2. Antonov A.G. The methodology of therapeutic hypothermia to children born in a state of asphyxia / A.G. Antonov, O.V. Ionov, A.R. Kirtbaya, E.N. Balashova, I.V. Nikitina, A.Y. Ryndin, E.V. Miroschnik, D.N. Degtyarev //Anesthesiology and Intensive Care. 2014; 59 (6): 76-7.

3. Ashwal S. Reparative effects of neural stem cells in neonatal rats with hypoxic-ischemic injury are not influenced by host sex / S. Ashwal, N. Ghosh, C.I. Turenius, M. Dulcich, C.M. Denham, B. Tone [et al.] // Pediatr. Res. 2014; 75(5): 603-11. https://doi.org/10.1038/pr.2014.7; PMid:24463490 PMCid:PMC4404035

4. Bae S.H. Long-lasting paracrine effects of human cord blood cells on damaged neocortex in an animal model of cerebral palsy / S.H. Bae, T.H. Kong, H.S. Lee, K.S. Kim, K.S. Hong, M. Chopp [et al.] // Cell Transplant. 2012; 21(11): 2497-515. https://doi.org/10.3727/096368912X640457; PMid:22524897

5. Bahr L. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation / L. Bahr, I. Batsis, G. Moll, M. Hagg, A. Szakos, Sundberg [et al.] // Stem Cells. 2012; 30(7): 1575-8. https://doi.org/10.1002/stem.1118; PMid:22553154

6. Baranov A.A. Premature babies in childhood and adolescence (medical and psychosocial research) / A.A. Baranov, V.Y. Albitsky, S.Y. Volgina, V.D. Mendelevich // M.; 2001; 184s.

7. Bohlin K. Cell-based strategies to reconstitute vital functions in preterm infants with organ failure. Best Pract. Res. / K. Bohlin //Clin. Obstet. Gynaecol. 2016; 31: 99-111. https://doi.org/10.1016/j.bpobgyn.2015.08.012; PMid:26527306

8. Borghesi A. Stem cell therapy for neonatal diseases associated with preterm birth / A. Borghesi, C. Cova, D.Gazzolo, M. Stronati // J. Clin. Neonatol. 2013; 2(1): 1-7. https://doi.org/10.4103/2249-4847.109230; PMid:24027735 PMCid:PMC3761956

9. Borlongan C.V. Central nervous system entry of peripherally infected umbilical cord blood cells is not required for neuroprotection in stroke / C.V. Borlongan, M. Hadman, C.D. Sanberg, P.R. Sanberg // Stroke. 2004; 35(10): 2385-9. https://doi.org/10.1161/01.STR.0000141680.49960.d7; PMid:15345799

10.Cameron S.H. Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia / S.H. Cameron, A.J. Alwakeel, L. Goddard., C.E. Hobbs, E.K. Gowing, E.R. Barnett [et al.] // Mol. Cell. Neurosci. 2015; 68: 56-72. https://doi.org/10.1016/j.mcn.2015.03.019; PMid:25828540

11. Carroll J. Human cord blood for the hypoxic-ischemic reonate // Pediatric Research. 2012; 71: P. 459–463. https://doi.org/10.1038/pr.2011.53; PMid:22278181 PMCid:PMC3640287

12. Chen L. Intracranial transplant of olfactory ensheathing cells in children and adolescents with cerebral palsy: a randomized controlled clinical trial / L. Chen, H. Huang, H. Xi, Z. Xie, R. Liu, Jiang Z. [et al.] //Cell Transplant. 2010; 19(2): 185-91. https://doi.org/10.3727/096368910X492652; PMid:20350360

13. Chua J.Y. Intra-arterial injection of neural stem cells using a microneedle technique does not cause microembolic strokes / J.Y. Chua, A.V. Pendharkar, N. Wang, R. Choi, R.H. Andres, X. Gaeta [et al.] //J. Cereb. Blood Flow Metab. 2011; 31(5): 1263-71. https://doi.org/10.1038/jcbfm.2010.213; PMid:21157474 PMCid:PMC3099630

14. Chou R.H. The potential therapeutic applications of olfactory ensheathing cells in regenerative medicine / R.H. Chou, C.Y. Lu., J.R. Fan, Y.L.Yu, W.C. Shyu // Cell Transplant. 2014; 23(4-5): 567-71. https://doi.org/10.3727/096368914X678508; PMid:24816451

15. Comi A.M. Neural stem cells reduce brain injury after unilateral carotid ligation. / A.M. Comi, E. Cho, J.D. Mulholland, A. Hooper, Q. Li, Y. Qu [et al.] // Pediatr. Neurol. 2008; 38(2): 86-92. https://doi.org/10.1016/j.pediatrneurol.2007.10.007; PMid:18206788

16. Constantin G. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis / G. Constantin, S. Marconi, B. Rossi, S. Angiari, L. Calderan, E. Anghileri [et al.] //Stem Cells. 2009; 27(10): 2624-35. https://doi.org/10.1002/stem.194; PMid:19676124

17. Cotten C.M. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy / C.M. Cotten, A.P. Murtha, R.N. Goldberg, C.A. Grotegut, P.B. Smith, R.F. Goldstein [et al.] // J. Pediatr. 2014; 164(5): 973-9. e1.

18. Cui L.L. The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity / L.L. Cui., E. Kerkela, A. Bakreen, F. Nitzsche, A. Andrzejewska, A. Nowakowski [et al.] // Stem Cell Res. Ther. 2015; 6: 11. https://doi.org/10.1186/scrt544; PMid:25971703 PMCid:PMC4429328

19. Daadi M.M. Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury / M.M. Daadi, A.S. Davis, A. Arac, Z. Li, A.L. Maag, R. Bhatnagar [et al.] //Stroke. 2010; 41(3): 516-23. https://doi.org/10.1161/STROKEAHA.109.573691; PMid:20075340

20. Danielyan L. Intranasal delivery of cells to the brain / L. Danielyan, R. Schafer, A. von Ameln-Mayerhofer, M. Buadze, J. Geisler, T. Klopfer [et al.] // Eur. J. Cell Biol. 2009; 88(6): 315-24. https://doi.org/10.1016/j.ejcb.2009.02.001; PMid:19324456

21. Davies M.W. Reference ranges for the linear dimensions of the intracranial ventricles in preterm neonates / M.W. Davies, M. Swaminathan, S.L. Chuang, F.R. Betheras // Arch. Dis. Child. Fetal Neonatal Ed. 2000; 82(3): F218-23. https://doi.org/10.1136/fn.82.3.F218; PMid:10794790 PMCid:PMC1721078

22. Donega V. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement / V. Donega, C. van Velthoven, C. Nijboer [et al.] // PLoS ONE. – 2013. – 8. – P. e51253. https://doi.org/10.1371/journal.pone.0051253; PMid:23300948 PMCid:PMC3536775

23. Donega V. Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse / V. Donega, C.H. Nijboer, C.T. van Velthoven, S.A. Youssef, A. de Bruin, F. van Bel [et al.] //Pediatr. Res. 2015; 78(5): 520-6. https://doi.org/10.1038/pr.2015.145; PMid:26270577 PMCid:PMC4635434

24. Donega V. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment / V. Donega, C.T. van Velthoven, C.H. Nijboer, A. Kavelaars, C.J. Heijnen // J. Cereb. Blood Flow Metab. 2013; 33(5): 625-34. https://doi.org/10.1038/jcbfm.2013.3; PMid:23403379 PMCid:PMC3652688

25. Donega V. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury / V. Donega, C.H. Nijboer, G. van Tilborg, R.M. Dijkhuizen, A. Kavelaars, C.J. Heijnen // Exp. Neurol. 2014; 261: 53-64. https://doi.org/10.1016/j.expneurol.2014.06.009; PMid:24945601

26. Efimova O. A. Molecular biology for bioinformatics /no10_epigenetika-1.ppt

27. Erices A. Mesenchymal progenitor cells in human umbilical cord blood /P.Conget, J.J. Minguell //J. Br. J. Haematol. 2000; 109(1): 235-42. https://doi.org/10.1046/j.1365-2141.2000.01986.x; PMid:10848804

28.Flax J.D. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes /S. Aurora, C.Yang, C. Simonin, A.M. Wills, L.L. Billinghurst et al. //Nat. Biotechnol. 1998; 16(11): 1033-9. https://doi.org/10.1038/3473; PMid:9831031

29. Gao J. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion /J.E. Dennis, R.F. Muzic, M. Lundberg, A.I. Caplan // Cells Tissues Organs. 2001; 169(1): 12-20. https://doi.org/10.1159/000047856; PMid:11340257

30. Greggio S. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in neonatal hypoxic-ischemic rats /S. de Paula,P.N. Azevedo, G.T. Venturin , J.C. Dacosta // Life Sci. 2014; 96(1-2): 33-9. https://doi.org/10.1016/j.lfs.2013.10.017; PMid:24177600

31. Guan L.X. Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes /H. Guan, H.B. Li, C.A. Ren, L. Liu, J.J. Chu et al. //Exp. Ther. Med. 2015; 9(5): 1623-30. https://doi.org/10.3892/etm.2015.2339

32. Gutierrez-Fernandez M. Functional recovery after hematic administration of allogenic mesenchymal stem cells in acute ischemic stroke in rats /B. Rodriguez-Frutos, J. Alvarez-Grech, M.T. Vallejo-Cremades, M. Exposito-Alcaide, J. Merino et al. //Neuroscience. 2011; 175: 394-405. https://doi.org/10.1016/j.neuroscience.2010.11.054; PMid:21144885

33. Guzman R. Intravascular cell replacement therapy for stroke /R. Choi, A. Gera, A. De Los Angeles, R.H. Andres, G.K. Steinberg //Neurosurg. Focus. 2008; 24(3-4): E15. https://doi.org/10.3171/FOC/2008/24/3-4/E14; PMid:18341391

34. Hass R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC /C. Kasper, S. Bohm, R. Jacobs //Cell Commun. Signal. 2011; 9: 12. https://doi.org/10.1186/1478-811X-9-12; PMid:21569606 PMCid:PMC3117820

35. Hirschi K.K. Induced pluripotent stem cells for regenerative medicine /S. Li, K. Roy //Annu. Rev. Biomed. Eng. 2014; 16: 277-94. https://doi.org/10.1146/annurev-bioeng-071813-105108; PMid:24905879 PMCid:PMC4287204

36. Hori J. Neural progenitor cells lack immunogenicity and resist destruction as allografts /T.F. Ng, M. Shatos, H. Klassen, J.W. Streilein, M.J. Young //Stem Cells. 2003; 21(4): 405-16. https://doi.org/10.1634/stemcells.21-4-405; PMid:12832694

37.http://dbyne.moy.su/news/kogda_vyrastjat_iskusstvennuju_pechen_i_pri_chem_tu/2014-06-25-162

38. http://sciencevsaging.org/content/свободный-/-9

39. http://biofile.ru/bio/19658.html

40. Iguchi A. Graft-versus-host disease (GVHD) prophylaxis by using methotrexate decreases pre-engraftment syndrome and severe acute GVHD, and accelerates engraftment after cord blood transplantation /Y. Terashita, M. Sugiyama, J. Ohshima, T.Z. Sato, Y. Cho et al. //Pediatr. Transplant. 2016; 20(1): 114-9. https://doi.org/10.1111/petr.12621; PMid:26526424

41. Imitola J. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway /K. Raddassi, K.I. Park, F.J. Mueller, M. Nieto, Y.D. Teng et al. //Proc. Natl. Acad. Sci. USA. 2004; 101(52): 18117-22. https://doi.org/10.1073/pnas.0408258102; PMid:15608062 PMCid:PMC536055

42. Janowski M. Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation /A. Lyczek, C. Engels, J. Xu, B. Lukomska, J.W. Bulte et al. //J. Cereb. Blood Flow Metab. 2013; 33(6): 921-7. https://doi.org/10.1038/jcbfm.2013.32; PMid:23486296 PMCid:PMC3677113

43. Jansen E.M. Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic-hypoxic brain injury in rats /L. Solberg, S. Underhill, S. Wilson, C. Cozzari, B.K. Hartman et al. //Exp. Neurol. 1997; 147(2): 487-97. https://doi.org/10.1006/exnr.1997.6596; PMid:9344572

44. Jin K. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat /Y. Sun, L. Xie, X.O. Mao, J. Childs, A. Peel et al. //Neurobiol. Dis. 2005; 18(2): 366-74. https://doi.org/10.1016/j.nbd.2004.10.010; PMid:15686965

45. Johnston M.V. Sex and the pathogenesis of cerebral palsy /H. Hagberg //Dev. Med. Child Neurol. 2007; 49(1): 74-8. https://doi.org/10.1017/S0012162207000199.x; PMid:17209983

46. Kao C.H. Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors /S.H. Chen, C.C. Chio, Lin M.T. Shock. 2008; 29(1): 49-55.v

47. Keroll D. The use of stem cells in hypoxic-ischemic brain damage of newborn pulp. Magazine «cell and organ transplantation» //2013; 1(1),

48. Kucia M. Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report /M. Halasa, M. Wysoczynski, M. Baskiewicz-Masiuk, S. Moldenhawer, E. Zuba-Surma et al. //Leukemia. 2007; 21(2): 297-303. https://doi.org/10.1038/sj.leu.2404470; PMid:17136117

49. Larijani B. Stem cell therapy in treatment of different diseases /E.N. Esfahani, P. Amini, B. Nikbin, K. Alimoghaddam, S. Amiri et al. //Acta Med. Iran. 2012; 50(2): 79-96. PMid:22359076

50. Le Blanc K. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study /F. Frassoni, L. Ball, F. Locatelli, H. Roelofs, I. Lewis, et al.//Lancet. 2008; 371(9624): 1579-86. https://doi.org/10.1016/s0140-6736(08)60690-x

51. Li L. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study /Q. Jiang, G. Ding, L. Zhang, Z.G. Zhang, Q. Li et al. //J. Cereb. Blood Flow Metab. 2010; 30(3): 653-62. https://doi.org/10.1038/jcbfm.2009.238; PMid:19888287 PMCid:PMC2844252

52. Lin R.Z. Functional endothelial progenitor cells from cryopreserved umbilical cord blood /A. Dreyzin, K. Aamodt, A.C. Dudley, J.M. Melero-Martin //Cell Transplant. 2011; 20(4): 515-22. https://doi.org/10.3727/096368910X532729; PMid:20887663 PMCid:PMC3036780

53. Li M. Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair /J.S. Hale, J.N. Rich, R.M. Ransohoff, J.D. Lathia //Trends Neurosci. 2012; 35(10): 619-28. https://doi.org/10.1016/j.tins.2012.06.003; PMid:22784557 PMCid:PMC3461091

54. Luan Z. Treatment of an infant with severe neonatal hypoxic-ischemic encephalopathy sequelae with transplantation of human neural stem cells into cerebral ventricle /G.Yin, X. Hu et al. // Zhonghua Erke Zazhi. 2005; 43: 580–583. PMid:16191266

55. Luan Z. Treatment of newborns with severe injured brain with transplantation of human neural precursor cells /W. Liu, S. Qu et al. //Zhonghua Erke Zazhi. 2011; 49: 445–449. PMid:21924058

56. Lundberg J. Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: engraftment is dependent on cell type and adhesion molecule expression /E. Sodersten, E. Sundstrom , K. Le Blanc, T. Andersson, O. Hermanson et al. //Cell Transplant. 2012; 21(1): 333-43. https://doi.org/10.3727/096368911X576036; PMid:21669035

57. Ma L. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients /Z. Zhou, D. Zhang, S. Yang, J. Wang, F. Xue et al. //Thromb. Haemost. 2012; 107(5): 937-50. https://doi.org/10.1160/TH11-08-0596; PMid:22398715

58. Ma S. Immunobiology of mesenchymal stem cells /N. Xie, W. Li, B. Yuan, Y. Shi, Y.Wang //Cell Death Differ. 2014; 21(2): 216-25. https://doi.org/10.1038/cdd.2013.158; PMid:24185619 PMCid:PMC3890955

59. Mancias-Guerra C. Safety and tolerability of intrathecal delivery of autologous bone marrow nucleated cells in children with cerebral palsy: an open-label phase I trial /A.R. Marroquin-Escamilla, O. Gonzalez-Llano, L. Villarreal-Martinez, J.C. Jaime-Perez, F. Garcia-Rodriguez et al. //Cytotherapy. 2014; 16(6): 810-20. https://doi.org/10.1016/j.jcyt.2014.01.008; PMid:24642016

60. Meier C. Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells /J. Middelanis, B. Wasielewski et al. //Pediatric Research. 2006; 59: 244-249. https://doi.org/10.1203/01.pdr.0000197309.08852.f5; PMid:16439586s

61. Misra V. Intra-arterial delivery of cell therapies for stroke /A. Lal, R. El Khoury, P.R. Chen, S.I. Savitz //Stem Cells Dev. 2012; 21(7): 1007-15. https://doi.org/10.1089/scd.2011.0612; PMid:22181047 PMCid:PMC3328761

62. Mitsialis S.A. Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges /S. Kourembanas //Semin. Perinatol. 2016; 40(3):138-51. https://doi.org/10.1053/j.semperi.2015.12.002; PMid:26778234 PMCid:PMC4808378

63. Murase S. Deleted in colorectal carcinoma and differentially expressed integrins mediate the directional migration of neural precursors in the rostral migratory stream /A.F. Horwitz //J. Neurosci. 2002; 22(9): 3568-79. PMid:11978833

64. Narogan M.V. Experience of extremely premature infants with intraventricular hemorrhage complicated by progressive hydrocephalus /L.D. Vorona, V.L. Petraki, A.G. Prityko, B.P. Simernitsky, R.I. Romanova, E.E. Sidorenko, L.V. Malyutina, A. Petrova //Russian Vestnik Perinatology and pediatrics. 2013; 58 (3): 25-9.

65. Najar M. The immunomodulatory potential of mesenchymal stromal cells: a story of a regulatory network /G. Raicevic, E. Crompot, H. Fayyad-Kazan, D. Bron, M.Toungouz et al // J. Immunother. 2016; 39(2): 45-59. https://doi.org/10.1097/CJI.0000000000000108; PMid:26849074

66. Naujock M. Molecular and functional analyses of motor neurons generated from human cord-blood-derived induced pluripotent stem cells /N. Stanslowsky, P. Reinhardt, J. Sterneckert, A. Haase, U. Martin et al. // Stem Cells Dev. 2014; 23(24): 3011-20. https://doi.org/10.1089/scd.2014.0180; PMid:25007389

67. Newell L.F., Flowers M.E., Gooley T.A., Milano F., Carpenter P.A., Martin P.J. et al. Characteristics of chronic GVHD after cord blood transplantation. Bone Marrow Transplant. 2013; 48(10): 1285-90. https://doi.org/10.1038/bmt.2013.48; PMid:23584444 PMCid:PMC3795867

68. Nimgaonkar M.T. A unique population of CD34+ cells in cord blood /R. Roscoe, J. Persichetti, W.B. Rybka, A. Winkelstein, E.D. Ball //Stem Cells. 1995; 13(2): 158-66. https://doi.org/10.1002/stem.5530130207; PMid:7540469

69.Northington F.J. Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke /ILAR //J. 2006; 47(1): 32-8. https://doi.org/10.1093/ilar.47.1.32; PMid:16391429

70. Obenaus A. Long-term magnetic resonance imaging of stem cells in neonatal ischemic injury /N. Dilmac, B.Tone, H.R. Tian, R. Hartman, M. Digicayliog et al. //Ann. Neurol. 2011; 69(2): 282-91. https://doi.org/10.1002/ana.22168; PMid:21387373 PMCid:PMC3069664

71. Palmer T.D. Cell culture. Progenitor cells from human brain after death /P.H. Schwartz, P. Taupin, B. Kaspar, S.A. Stein, F.H. Gage //Nature. 2001; 411(6833): 42-3. https://doi.org/10.1038/35075141; PMid:11333968

72. Paula S. The dose-response effect of acute intravenous transplantation of human umbilical cord blood cells on brain damage and spatial memory deficits in neonatal hypoxia-ischemia /S. Greggio, D.R. Marinowic, D.C. Machado, J.C. DaCosta //Neuroscience. 2012; 210: 431-41. https://doi.org/10.1016/j.neuroscience.2012.03.009; PMid:22441035

73. Pendharkar A.V. Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia /J.Y. Chua, R.H. Andres, N. Wang, X. Gaeta, H. Wang et al. //Stroke. 2010; 41(9): 2064-70. https://doi.org/10.1161/STROKEAHA.109.575993; PMid:20616329 PMCid:PMC4831577

74.Perlman J.M. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy //Pediatrics. 2006; 117(3, Pt 2): 28-33.

75. Poltavtseva R.A. In vitro development of neural progenitor cells from human embryos. /A.A. Rzhaninova, A.V. Revishchin, M.A. Aleksandrova, L.I. Korochkin, V.S. Repin et al. //Bull. Exp. Biol. Med. 2001; 132(3): 861-3. https://doi.org/10.1023/A:1013170701936; PMid:11740578

76. Poltavtseva R.A. Evaluation of progenitor cell cultures from human embryos for neurotransplantation /M.V. Marey, M.A. Aleksandrova, A.V. Revishchin, L.I. Korochkin, G.T. Sukhikh //Brain Res. Dev. Brain Res. 2002; 134(1-2): 149-54. https://doi.org/10.1016/S0165-3806(02)00274-2

77. Popkov V.A. Diseases and aging: gender matters /E.Y. Plotnikov, D.N. Silachev, L.D. Zorova, I.B. Pevzner, S.S. Jankauskas et al. //Biochemistry (Mosc). 2015; 80(12): 1560-70. https://doi.org/10.1134/S0006297915120032; PMid:26638680

78. Reinders M.E. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study /G.J. Dreyer, J.R. Bank, H. Roelofs, S. Heidt, D.L. Roelen et al. //J. Transl. Med. 2015; 13: 344. https://doi.org/10.1186/s12967-015-0700-0; PMid:26537851 PMCid:PMC4632480

79. Rice J. The influence of immaturity on hypoxic-ischemic brain damage in the rat /R. Vannucci, J. Brierly //Ann Neurol. 1981; 9: 131–141. https://doi.org/10.1002/ana.410090206; PMid:7235629

80. Rocha V. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling /J.E.Jr. Wagner, K.A. Sobocinski, J.P. Klein, M.J. Zhang, M.M. Horowitz et al. //Eurocard and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N. Engl. J. Med. 2000; 342(25): 1846-54. https://doi.org/10.1056/NEJM200006223422501; PMid:10861319

81. Rosado-de-Castro P.H. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients /Fda R. Schmidt, V. Battistella, S.A. Lopes de Souza, B. Gutfilen, R.C. Goldenberg et al. //Regen. Med. 2013; 8(2): 145-55. https://doi.org/10.2217/rme.13.2; PMid:23477395

82. Rosenkranz K. The chemokine SDF-1/CXCL12 contributes to the ‘homing’ of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain /S. Kumbruch, K. Lebermann, K. Marschner, A. Jensen, R. Dermietzel et al. //J. Neurosci. Res. 2010; 88(6): 1223-33. PMid:19937807

83. Santilli G. Mild hypoxia enhances proliferation and multipotency of human neural stem cells /G. Lamorte, L. Carlessi, D. Ferrari, L. Rota Nodari, E. Binda et al. /PLoS One. 2010; 5(1): e8575. https://doi.org/10.1371/journal.pone.0008575; PMid:20052410 PMCid:PMC2797394

84. Silachev D.N. Evaluation of a long-term sensomotor deficit after neonatal rat brain ischemia/hypoxia /M.I. Shubina, S.S. Iankauskas, V.P. Mkrtchian, V.N. Manskikh, M.V. Guliaev, D.B. Zorov //Vyssh Nerv Deiat Im I P Pavlova. 2013; 63(3): 405-16.

85. Silachev D.N. Neuroprotective effect of glutamate-substituted analog of gramicidin A is mediated by the uncoupling of mitochondria /L.S. Khailova, V.A. Babenko, M.V. Gulyaev, S.I. Kovalchuk, L.D. Zorova et al. //Biochim. Biophys. Acta. 2014; 1840(12): 3434-42.

86. Silachev D.N. Intra-arterial administration of multipotent mesenchymal stromal cells promotes functional recovery of the brain after traumatic brain injury /E.Y. Plotnikov, V.A. Babenko, T.I. Danilina, L.D. Zorov, I.B. Pevzner et al. //Bull. Exp. Biol. Med. 2015; 159(4): 528-33. https://doi.org/10.1007/s10517-015-3009-3; PMid:26388566

87. Schu S. Immunogenicity of allogeneic mesenchymal stem cells /M. Nosov, L. O’Flynn, G. Shaw, O. Treacy, F. Barry et al. //J. Cell. Mol. Med. 2012; 16(9): 2094-103. https://doi.org/10.1111/j.1582-4934.2011.01509.x; PMid:22151542 PMCid:PMC3822979

88. Shea K.L. What can you do to protect the newborn brain? /A. Palanisamy //Curr. Opin. Anaesthesiol. 2015; 28(3): 261-6. https://doi.org/10.1097/ACO.0000000000000184; PMid:25827279

89. Shipounova I.N. Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation /N.A. Petinati, A.E. Bigildeev, E.A. Zezina, N.I. Drize, L.A. Kuzmina et al. //Biochemistry (Mosc). 2014; 79(12): 1363-70. https://doi.org/10.1134/S0006297914120104; PMid:25716730

90. Sukhikh G.T. Prospects for using stem and progenitor cells in the therapy of consequences of neonatal hypoxic-ischemic encephalopathy /D.N. Silachyov, I.B. Pevzner, L.D. Zorova, V.A. Babenko, V.A. Popkov, S.S. Yankausjkas, V.V. Zubkov, D.B. Zorov, E.Yu. Plotnikov //Obstetrics and gynecology. 2015; 5: 55-66.

91. Sun J. Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders /J. Allison, C. McLaughlin, L. Sledge, B. Waters-Pick, S. Wease et al. //Transfusion. 2010; 50(9): 1980-7. https://doi.org/10.1111/j.1537-2995.2010.02720.x; PMid:20546200 PMCid:PMC3816574

92. Svendsen C.N. Human neural stem cells: isolation, expansion and transplantation /M.A. Caldwell, T. Ostenfeld //Brain Pathol. 1999; 9(3): 499-513. https://doi.org/10.1111/j.1750-3639.1999.tb00538.x; PMid:10416990

93. Takahashi M. Large-scale reorganization of corticofugal fibers after neonatal hemidecortication for functional restoration of forelimb movements /A. Vattanajun, T. Umeda, K. Isa, T. Isa //Eur. J. Neurosci. 2009; 30(10): 1878-87. https://doi.org/10.1111/j.1460-9568.2009.06989.x; PMid:19895560

94. Takahashi K. Induced pluripotent stem cells in medicine and biology /S. Yamanaka //Development. 2013; 140: 2257–2267. https://doi.org/10.1242/dev.092551; PMid:23715538

95. Taguchi A. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model /T. Soma, H. Tanaka, T. Kanda, H. Nishimura, H.Yoshikawa et al. //J. Clin. Invest. 2004; 114(3): 330-8. https://doi.org/10.1172/JCI200420622; PMid:15286799 PMCid:PMC484977

96. Thorne R.G. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations /W.H. Frey //2nd. Clin. Pharmacokinet . 2001; 40(12): 907-46. https://doi.org/10.2165/00003088-200140120-00003; PMid:11735609

97. Titomanlio L. Stem cell therapy for neonatal brain injury: perspectives and challenges /A. Kavelaars, J. Dalous, S. Mani, V. Ghouzzi, C. Heijnen et al. //Ann. Neurol. 2011; 70(5): 698-712. https://doi.org/10.1002/ana.22518

98. Uccelli A. Mesenchymal stem cells exert a remarkable regenerative effect requiring minimal CNS integration: commentary on: «Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function» by Voulgari-Kokota et al. //Exp. Neurol. 2013; 247: 292-5. https://doi.org/10.1016/j.expneurol.2013.01.028; PMid:23384664

99. Van Velthoven C. Nasal administration of stem cells: a promising novel route for ischemic brain damage /A. Kavelaars, F. van Bel, C. Heijnen //Pediatric Research. 2010; 68: 419–422. https://doi.org/10.1203/pdr.0b013e3181f1c289

100. Van Velthoven C. Mesenchymal stem cells as a treatment for neonatal ischemia /A. Kavelaars, C. Heijnen //Pediatric Research. 2012; 71: 474–481. https://doi.org/10.1038/pr.2011.64; PMid:22430383

101. Verina T. Pluripotent possibilities: human umbilical cord blood cell treatment after neonatal brain injury /A. Fatemi, M.V. Johnston, A.M. Comi //Pediatr. Neurol. 2013; 48(5): 346-54. https://doi.org/10.1016/j.pediatrneurol.2012.10.010

102. Wang Y. SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model /Y. Deng, G.Q. Zhou // Brain Res. 2008; 1195: 104-12. https://doi.org/10.1016/j.brainres.2007.11.068; PMid:18206136

103. Wang D. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience /H. Zhang, J. Liang, X. Li, X. Feng, H. Wang et al. //Cell Transplant. 2013; 22(12): 2267-77. PMid:24388428

104.Wang Q. Comparative analysis of human mesenchymal stem cells from fetal-bone marrow, adipose tissue, and Warton’s jelly as sources of cell immunomodulatory therapy /Q. Yang, Z. Wang, H. Tong, L. Ma, Y. Zhang et al. //Hum. Vaccin. Immunother. 2016; 12(1): 85-96. https://doi.org/10.1080/21645515.2015.1030549; PMid:26186552 PMCid:PMC4962749

105. Wang X. Umbilical cord blood cells regulate the differentiation of endogenous neural stem cells in hypoxic ischemic neonatal rats via the hedgehog signaling pathway /Y. Zhao, X. Wang //Brain Res. 2014; 1560: 18-26. https://doi.org/10.1016/j.brainres.2014.02.019; PMid:24565927

106. Wasielewski B. Neuroglial activation and CX43 expression are reduced upon transplantation of human umbilical cord blood cells after perinatal hypoxic-ischemic injury /A. Jensen, A. Roth-Harer et al. //Brain Research. 2012; 1487: 39–53. https://doi.org/10.1016/j.brainres.2012.05.066; PMid:22796290

107. Willing A.E. Intravenous versus intrastriatal cord blood administration in a rodent model of stroke /J. Lixian, M. Milliken, S. Poulos, T. Zigova, S. Song et al. // J. Neurosci. Res. 2003; 73(3): 296-307. https://doi.org/10.1002/jnr.10659; PMid:12868063

108. Yasuhara T. Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury /N. Matsukawa, G. Yu, L. Xu, R.W. Mays, J. Kovach et al. //Cell Transplant. 2006; 15(3): 231-8. https://doi.org/10.3727/000000006783982034; PMid:16719058

109. Yoo S.W. Immune following suppression mesenchymal stem cell transplantation in the ischemic brain is mediated by TGF-beta /D.Y. Chang, H.S. Lee, G.H. Kim, J.S. Park, B.Y. Ryu et al. //Neurobiol. Dis. 2013; 58: 249-57. https://doi.org/10.1016/j.nbd.2013.06.001; PMid:23759293

110. Zhang X. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy /Q. Zhang, W. Li, D. Nie, W. Chen, C. Xu et al.. //J. Neurosci. Res. 2014; 92(1): 35-45. https://doi.org/10.1002/jnr.23304; PMid:24265136

111. Zhang R. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury /Y. Liu, K. Yan, L. Chen, X.R. Chen, P. Li et al. //J. Neuroinflammation. 2013; 10: 106. https://doi.org/10.1186/1742-2094-10-106; PMid:23971414 PMCid:PMC3765323

112. Zhao L. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats /W. Duan, M. Reyes et al. // Experimental Neurology. 2002; .174: 11–20. https://doi.org/10.1006/exnr.2001.7853; PMid:11869029

113. Zwijnenburg P.J. Experimental pneumococcal meningitis in mice: a model of intranasal infection /T. van der Poll, S. Florquin, S.J. van Deventer, J.J. Roord, A.M. van Furth // J. Infect. Dis. 2001; 183(7): 1143-6. https://doi.org/10.1086/319271; PMid:11237845