Feasibility and safety of intrathecal transplantation of autologous bone marrow mesenchymal stem cells in horses

BMC Veterinary Research

Rogério Martins Amorim³  Guilherme Dias Melo¹  Gisele Fabrino Machado¹  Carolina Nogueira de Moraes²  Marilda Onghero Taffarel⁴  Fernanda da Cruz Landim- Alvarenga²  Leandro Maia² 

[1] Department of Clinic, Surgery and Animal Reproduction, São Paulo State University, Clóvis Pestano, 793, CEP: 16050-680, Araçatuba, São Paulo, Brazil;Department of Animal Reproduction, São Paulo State University, District of Rubião Júnior, n/n, CEP: 18618970, Botucatu, São Paulo, Brazil;Department of Veterinary Clinics, São Paulo State University, District of Rubião Júnior, n/n, CEP: 18618970, Botucatu, São Paulo, Brazil;Department of Veterinary Medicine, Maringá State University, Av. Colombo, 5.790, CEP: 87020-900, Maringá, Paraná, Brazil

关键词: Neurology;    Matrix metalloproteinases;    Horse;    Transplantation;    Mesenchymal stem cells;   

Others  :  1140514
DOI  :  10.1186/s12917-015-0361-5

 received in 2014-08-07, accepted in 2015-02-13,  发布年份 2015

【 摘 要 】

Background

Recent studies have demonstrated numerous biological properties of mesenchymal stem cells and their potential application in treating complex diseases or injuries to tissues that have difficulty regenerating, such as those affecting the central and peripheral nervous system. Thus, therapies that use mesenchymal stem cells are promising because of their high capacity for self-regeneration, their low immunogenicity, and their paracrine, anti-inflammatory, immunomodulatory, anti-apoptotic and neuroprotective effects. In this context, the purpose of this study was to evaluate the feasibility and safety of intrathecal transplantation of bone marrow-derived mesenchymal stem cells in horses, for future application in the treatment of neurological diseases.

Results

During the neurological evaluations, no clinical signs were observed that were related to brain and/or spinal cord injury of the animals from the control group or the treated group. The hematological and cerebrospinal fluid results from day 1 and day 6 showed no significant differences (P > 0.05) between the treated group and the control group. Additionally, analysis of the expression of matrix metalloproteinase (MMP) -2 and −9 in the cerebrospinal fluid revealed only the presence of pro-MMP-2 (latent), with no significant difference (P > 0.05) between the studied groups.

Conclusions

The results of the present study support the hypothesis of the feasibility and safety of intrathecal transplantation of autologous bone marrow-derived mesenchymal stem cells, indicating that it is a promising pathway for cell delivery for the treatment of neurological disorders in horses.

【 授权许可】

   
2015 Maia et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Wright KT, Masri WE, Osman A, Chowdhury J, Johnson WEB: Concise review: bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications. Stem Cell 2011, 29:169-78.
• [2]Baraniak PR, McDevitt TC: Stem cell paracrine actions and tissue regeneration. Regen Med 2010, 5:121-43.
• [3]Vidal MA, Robinson SO, Lopez MJ, Paulsen DB, Borkhsenious Johnson JR, Moore RM, et al.: Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg 2008, 37:713-24.
• [4]Crovace A, Lacitignola L, De Siena R, Rossi G, Francioso E: Cell therapy for tendon repairin horses: an experimental study. Vet Res Commun 2007, 31:281-3.
• [5]Pacini S, Spinabella S, Trombi L, Galimberti S, Dini F, Carulicci F, et al.: Suspension of bone marrow-derived undifferentiae mesenchymal stromal cells for repair of superficial digital flexor tendon in race horses. Tissue Eng 2007, 13:2949-55.
• [6]Wilke MM, Nydam DV, Nixon AJ: Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res 2007, 25:913-25.
• [7]Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL: Effect of adipose-derived nucleated cell fractions on tendon repair in horseswith collagenase-induced tendinitis. Am J Vet Res 2008, 69:928-37.
• [8]Carvalho AM, Alves ALG, Oliveira PGG, Alvarez LEC, Laufer-Amorim R, Hussni CA, et al.: Use of adipose tissue-derived mesenchymal stem cells for experimental tendinitis therapy in equines. J Equine Vet Sci 2011, 31:26-34.
• [9]McIlwraith CW, Frisbie DD, Rodkey WG, Kisiday JD, Werpy NM, Kawcak CE, et al.: Evaluation of intra-articular mesenchymal stem cells to augment healing of microfractured chondral defects. Arthroscopic 2011, 27:1552-61.
• [10]Zhang J, Li Y, Chen J, Lu M, Elias SB, Mitchell JB, et al.: Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005, 195:16-26.
• [11]Mayhew IG, De Lahunta A, Whitlock RH: Spinal cord disease in the horse. The Cornell Vet 1978, 68:1-207.
• [12]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krauses D, et al.: Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 2006, 8:315-7.
• [13]Carvalho AM, Alves ALG, Golim MA, Moroz A, Hussni CA, Oliveira PGG, et al.: Isolation and immunophenotypic characterization of mesenchymal stem cells derived from equine species adipose tissue. Vet Immunol Immunop 2009, 132:303-6.
• [14]Arnhold SJ, Goletz I, Klein H, Stumpf G, Beluche LA, Rohde C, et al.: Isolation and characterization of bone marrow–derived equine mesenchymal stem cells. Am J Vet Res 2007, 68:1095-105.
• [15]Guest DJ, Ousey JC, Smith MRW: Defining the expression of marker genes in equine mesenchymal stromal cells. Stem Cells and Cloning: Adv Appl 2008, 2008:1-9.
• [16]Radcliffe CH, Flaminio JBF, Fortier L: Temporal analysis of equine bone marrow aspirate during establishment of putative mesenchymal progenitor cell populations. Stem Cells Dev 2010, 19:269-82.
• [17]Martinello T, Bronzini I, Maccatrozoo L, Lacopetti I, Sampaolesi M, Mascarello F, et al.: Cryopreservation does not affect the stem characteristics of multipotent cells isolated from equine peripheral blood. Tissue Eng Part C 2010, 16:771-81.
• [18]Hoynowski SM, Fry MM, Gardner BM, Leming MT, Tucker JR, Black L, et al.: Characterization and differentiation of equine umbilical cord-derived matrix cells. Biochem Biophys Res Commun 2007, 362:347-53.
• [19]Iacono E, Brunori L, Pirrone A, Pagliaro PP, Ricci F, Tazzari PL, et al.: Isolation, characterization and differentiation of mesenchymal stem cells from amniotic fluid, umbilical cord blood and Wharton’s jelly in the horse. Reproduction 2012, 143:455-68.
• [20]Mensing N, Gasse H, Hambruch N, Haeger JD, Pfarrer C, Staszyk C: Isolation and characterization of multipotent mesenchymal stromal cells from the gingiva and the periodontal ligament of the horse. BMC Vet Res 2011, 7:1-42. BioMed Central Full Text
• [21]Dimarakis I, Levicar N: Cell culture medium composítion and translational adult bone marrow-derived stem cell research. Stem Cells 2006, 24:1407-8.
• [22]Sotiropoulou PA, Perez SA, Salagianni M, Baxevanis CN, Papamichail M: Cell culture medium composítion and translational adult bone marrow-derived stem cell research. Stem Cells 2006, 24:1409-10.
• [23]Toupadakis CA, Woung A, Genetos DC, Cheung WK, Borjesson DL, Leach JK, et al.: Comparison of the osteogenic potential of equine mesenchymal stem cells from bone marrow, adipose tissue, umbilical cord blood, and umbilical cord tissue. Am J Vet Res 2010, 71:1237-45.
• [24]Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, et al.: Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther 2011, 2:1-13. BioMed Central Full Text
• [25]Yang WZ, Zhang Y, Wu F, Min WP, Minev B, Zhang M, et al.: Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy form degenerative conditions. J Transl Med 2010, 8:1-6. BioMed Central Full Text
• [26]Kaneko JJ, Harvey JW, Bruss ML: Clinical biochemistry of domestic animals. Elsevier, Burlington; 2008.
• [27]Green E, Constantinescu G, Kroll R: Equine cerebrospinal fluid: Analysis. Compend Contin Educ Pract Vet 1993, 15:288-301.
• [28]Mayhew IG, Whitlock RH, Tasker JB: Equine cerebrospinal fluid: reference values of normal horses. Am J Vet Res 1977, 38:1271-4.
• [29]Melo GD, Marcondes M, Machado GF: Canine cerebral leishmaniasis: potential role of matrix metalloproteinase-2 in the development of neurological disease. Vet Immunol Immunopathol 2012, 148:260-6.
• [30]Verma PR, Hansch C: Matrix metalloproteinases (MMPs): chemical–biological functions and (Q) SARs. Bioorg Med Chem 2007, 15:2223-68.
• [31]Rosenberg GA: Matrix metalloproteinases in neuroinflammation. Glia 2002, 39:279-91.
• [32]Bergman RL, Inzana KD, Inzana TJ: Characterization of matrix metalloproteinase-2 and −9 in cerebrospinal fluid of clinically normal dogs. Am J Vet Res 2002, 63:1359-62.
• [33]Grossete M, Phelps J, Arko L, Yonas H, Rosemberg GA: Elevation of MMP-3 and MMP-9 in CSF and blood in patients with severe traumatic brain injury. Neurosurgery 2009, 65:702-4.
• [34]Leppert D, Leib SL, Grygar C, Miller KM, Schaad UB, Holländer GA: Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood–brain barrier damage and neurological sequelae. Clin Infect Dis 2000, 31:80-4.
• [35]Williams PL, Leib SL, Kamberi P, Leppert D, Sobel RA, Bifrare Y, et al.: Levels of matrix metalloproteinase–9 within cerebrospinal fluid in a rabbit model of coccidioidal meningitis and vasculitis. J Infect Dis 2002, 186:1692-5.
• [36]Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S, et al.: Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 1998, 121:2327-34.
• [37]Barreira APB, Bacellar DTL, Kiffer RG, Alves ALG: Punção aspirativa de medula óssea em equinos adultos para obtenção de células-tronco. Rev Bras Ciênc 2008, 15:56-9.
• [38]Maia L, Landim-Alvarenga FC, Golim MA, Sudano MJ, Taffarel MO, De Vita B, et al.: Potential of neural transdifferentiation of mesenchymal stem cells from equine bone marrow. Pesq Vet Bras 2012, 32:444-52.
• [39]Maia L, Landim-Alvarenga FC, Da Mota LS, De Assis Golim M, Laufer-Amorim R, De Vita B, et al.: Immunophenotypic, immunocytochemistry, ultrastructural, and cytogenetic characterization of mesenchymal stem cells from equine bone marrow. Microsc Res Tech 2013, 5:618-24.
• [40]Mayhew IG: Collection of cerebrospinal fluid from the horse. Cornell Vet 1975, 65:500-11.
• [41]Malikides N, Hodgson DR, Rose RJ: Neurology. In Manual Equine Practice. 2nd edition. Edited by Rose RJ, Hodgson DR. Saunders, Philadelphia; 2000:503-75.
• [42]Mayhew IGJ: Neurologic Evaluation. In Large Animal Neurology. 2nd edition. Edited by Mayhew IGJ. Wiley-Blackwell Publishing, West Sussex; 2009:11-46.
• [43]Marangoni NR, Melo GD, Moraes OC, Souza MS, Perri SHV, Machado GF: Levels of matrix metalloproteinase-2 and −9 in the cerebrospinal fluid of dogs with visceral leishmaniasis. Parasite Immunol 2011, 33:330-4.
• [44]SAS Institute Inc: SAS/IML 9.3 User’s Guide. SAS Institute Inc, Cary, NC; 2011.