International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

Mesenchymal Stem Cell Transplantation Promotes Functional Recovery through MMP2/STAT3 Related Astrogliosis after Spinal Cord Injury

  • Kim, Choonghyo (Department of Neurosurgery, Kangwon National University School of Medicine) ;
  • Kim, Hee Jung (Department of Neurosurgery, Kangwon National University School of Medicine) ;
  • Lee, Hyun (Divisions of Applied Animal Science and Animal Resource Science, Department of Animal Life Science, Kangwon National University) ;
  • Lee, Hanbyeol (Department of Thoracic and Cardiovascular Surgery, Kangwon National University School of Medicine) ;
  • Lee, Seung Jin (Department of Neurosurgery, Kangwon National University School of Medicine) ;
  • Lee, Seung Tae (Divisions of Applied Animal Science and Animal Resource Science, Department of Animal Life Science, Kangwon National University) ;
  • Yang, Se-Ran (Department of Thoracic and Cardiovascular Surgery, Kangwon National University School of Medicine) ;
  • Chung, Chun Kee (Department of Neurosurgery, Seoul National University College of Medicine)
  • Received : 2018.12.15
  • Accepted : 2019.05.17
  • Published : 2019.07.31
⟨ Previous Next ⟩

Abstract

Background and Objectives: Treatment with mesenchymal stem cells (MSC) in spinal cord injury (SCI) has been highlighted as therapeutic candidate for SCI. Although astrogliosis is a major phenomenon after SCI, the role of astrogliosis is still controversial. In this study, we determined whether acute transplantation of MSC improves the outcome of SCI through modulating astrogliosis. Methods: Bone marrow derived rat MSCs were induced neural differentiation and transplanted after acute SCI rats. Matrix metalloproteinase (MMP) and neuro-inflammatory pathway were analyzed for acute astrogliosis at 1, 3 and 7 d after SCI in RT-PCR- and western blot analysis. Functional outcome was assessed serially at postoperative 1 d and weekly for 4 weeks. Histopathologic analysis was undertaken at 7 and 28 d following injury in immunohistochemistry. Results: Transplantation of MSCs decreased IL-1α, CXCL-2, CXCL-10, TNF-α and TGF-β in a rat model of contusive SCI. Protein level of NF-κB p65 was slightly decreased while level of STAT-3 was increased. In immunohistochemistry, MSC transplantation increased acute astrogliosis whereas attenuated scar formation with increased sparing white matter of spinal cord lesions. In RT-PCR analysis, mRNA levels of MMP2 was significantly increased in MSC transplanted rats. In BBB locomotor scale, the rats of MSC treated group exhibited improvement of functional recovery. Conclusions: Transplantation of MSC reduces the inflammatory reaction and modulates astrogliosis via MMP2/STAT3 pathway leading to improve functional recovery after SCI in rats.

Keywords

Acknowledgement

This work was supported by National Research Foundation (NRF) of the Korean government (2017R1D1A1A02019187, NRF-2017R1A2B4006197).

References

  1. Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, Agrawal A, Adeleye AO, Shrime MG, Rubiano AM, Rosenfeld JV, Park KB. Estimating the global incidence of traumatic brain injury. J Neurosurg 2018 [Epub ahead of print]
  2. Wyndaele M, Wyndaele JJ. Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord 2006;44:523-529 https://doi.org/10.1038/sj.sc.3101893
  3. Rossignol S, Schwab M, Schwartz M, Fehlings MG. Spinal cord injury: time to move? J Neurosci 2007;27:11782-11792 https://doi.org/10.1523/JNEUROSCI.3444-07.2007
  4. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 2009;32:638-647 https://doi.org/10.1016/j.tins.2009.08.002
  5. Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ. Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist 2010;16: 156-170 https://doi.org/10.1177/1073858409355830
  6. Zhang H, Chang M, Hansen CN, Basso DM, Noble-Haeusslein LJ. Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 2011;8:206-220 https://doi.org/10.1007/s13311-011-0038-0
  7. Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 2002;99:2199-2204 https://doi.org/10.1073/pnas.042678299
  8. Parr AM, Kulbatski I, Wang XH, Keating A, Tator CH. Fate of transplanted adult neural stem/progenitor cells and bone marrow-derived mesenchymal stromal cells in the injured adult rat spinal cord and impact on functional recovery. Surg Neurol 2008;70:600-607; discussion 607 https://doi.org/10.1016/j.surneu.2007.09.043
  9. Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM, Kawaguchi R, Coppola G, Khakh BS, Deming TJ, Sofroniew MV. Astrocyte scar formation aids central nervous system axon regeneration. Nature 2016;532:195-200 https://doi.org/10.1038/nature17623
  10. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 2004; 24:2143-2155 https://doi.org/10.1523/JNEUROSCI.3547-03.2004
  11. Okada S, Hara M, Kobayakawa K, Matsumoto Y, Nakashima Y. Astrocyte reactivity and astrogliosis after spinal cord injury. Neurosci Res 2018;126:39-43 https://doi.org/10.1016/j.neures.2017.10.004
  12. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 2013;33:12870-12886 https://doi.org/10.1523/JNEUROSCI.2121-13.2013
  13. Poon PC, Gupta D, Shoichet MS, Tator CH. Clip compression model is useful for thoracic spinal cord injuries: histologic and functional correlates. Spine (Phila Pa 1976) 2007;32:2853-2859 https://doi.org/10.1097/BRS.0b013e31815b7e6b
  14. Rivlin AS, Tator CH. Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 1978;10:38-43
  15. Han NR, Yun JI, Park YH, Ahn JY, Kim C, Choi JH, Lee E, Lim JM, Lee ST. Generation of priming mesenchymal stem cells with enhanced potential to differentiate into specific cell lineages using extracellular matrix proteins. Biochem Biophys Res Commun 2013;436:413-417 https://doi.org/10.1016/j.bbrc.2013.05.116
  16. Jiang J, Lv Z, Gu Y, Li J, Xu L, Xu W, Lu J, Xu J. Adult rat mesenchymal stem cells differentiate into neuronal-like phenotype and express a variety of neuro-regulatory molecules in vitro. Neurosci Res 2010;66:46-52 https://doi.org/10.1016/j.neures.2009.09.1711
  17. Rabchevsky AG, Fugaccia I, Sullivan PG, Scheff SW. Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing. J Neurotrauma 2001;18:513-522 https://doi.org/10.1089/089771501300227314
  18. Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Res Bull 1999;49:377-391 https://doi.org/10.1016/S0361-9230(99)00072-6
  19. Clausen F, Lorant T, Lewen A, Hillered L. T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. J Neurotrauma 2007;24:1295-1307 https://doi.org/10.1089/neu.2006.0258
  20. McTigue DM, Sahinkaya FR. The fate of proliferating cells in the injured adult spinal cord. Stem Cell Res Ther 2011;2:7 https://doi.org/10.1186/scrt48
  21. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 2005;202:145-156 https://doi.org/10.1084/jem.20041918
  22. All AH, Bazley FA, Gupta S, Pashai N, Hu C, Pourmorteza A, Kerr C. Human embryonic stem cell-derived oligodendrocyte progenitors aid in functional recovery of sensory pathways following contusive spinal cord injury. PLoS One 2012;7:e47645 https://doi.org/10.1371/journal.pone.0047645
  23. Cusimano M, Biziato D, Brambilla E, Donega M, Alfaro-Cervello C, Snider S, Salani G, Pucci F, Comi G, Garcia-Verdugo JM, De Palma M, Martino G, Pluchino S. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain 2012;135:447-460 https://doi.org/10.1093/brain/awr339
  24. Sassoli C, Nosi D, Tani A, Chellini F, Mazzanti B, Quercioli F, Zecchi-Orlandini S, Formigli L. Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells. Exp Cell Res 2014;323:297-313 https://doi.org/10.1016/j.yexcr.2014.03.003
  25. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol 2014;34:132-143 https://doi.org/10.1016/j.matbio.2013.10.003
  26. Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, Rao JS. Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neurobiol Dis 2009;36:200-212 https://doi.org/10.1016/j.nbd.2009.07.012
  27. Renault-Mihara F, Mukaino M, Shinozaki M, Kumamaru H, Kawase S, Baudoux M, Ishibashi T, Kawabata S, Nishiyama Y, Sugai K, Yasutake K, Okada S, Nakamura M, Okano H. Regulation of RhoA by STAT3 coordinates glial scar formation. J Cell Biol 2017;216:2533-2550 https://doi.org/10.1083/jcb.201610102
  28. Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol 2016;37:608-620 https://doi.org/10.1016/j.it.2016.06.006
  29. Song K, Li W, Li M. Acute promyelocytic leukemia following autologous bone marrow-derived mesenchymal stem cell transplantation for traumatic brain injury: a case report. Oncol Lett 2015;10:2905-2908 https://doi.org/10.3892/ol.2015.3636
  30. Cheriyan T, Ryan DJ, Weinreb JH, Cheriyan J, Paul JC, Lafage V, Kirsch T, Errico TJ. Spinal cord injury models: a review. Spinal Cord 2014;52:588-595 https://doi.org/10.1038/sc.2014.91
  31. Fehlings MG, Tator CH. The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 1995;132: 220-228 https://doi.org/10.1016/0014-4886(95)90027-6
  32. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E, Leo-Summers L, Maroon J, Marshall LF, Perot PL, Piepmeier J, Sonntag VKH, Wagner FC, Wilberger JE, Winn HR. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405-1411 https://doi.org/10.1056/NEJM199005173222001
  33. Fehlings MG, Vaccaro A, Wilson JR, Singh A, W Cadotte D, Harrop JS, Aarabi B, Shaffrey C, Dvorak M, Fisher C, Arnold P, Massicotte EM, Lewis S, Rampersaud R. Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One 2012;7:e32037 https://doi.org/10.1371/journal.pone.0032037
  34. Lee H, Han NR, Hwang JY, Yun JI, Kim C, Park KH, Lee ST. Gelatin Directly enhances neurogenic differentiation potential in bone marrow-derived mesenchymal stem cells without stimulation of neural progenitor cell proliferation. DNA Cell Biol 2016;35:530-536 https://doi.org/10.1089/dna.2016.3237
  35. Park YH, Yun JI, Han NR, Park HJ, Ahn JY, Kim C, Choi JH, Lee E, Lim JM, Lee ST. Mass production of early-stage bone-marrow-derived mesenchymal stem cells of rat using gelatin-coated matrix. Biomed Res Int 2013;2013:347618

Cited by

  1. The expression of Th9 and Th22 cells in rats with cerebral palsy after hUC-MSC transplantation vol.83, pp.1, 2020, https://doi.org/10.1097/jcma.0000000000000202
  2. Intracerebroventricular Delivery of Human Umbilical Cord Mesenchymal Stem Cells as a Promising Therapy for Repairing the Spinal Cord Injury Induced by Kainic Acid vol.16, pp.1, 2020, https://doi.org/10.1007/s12015-019-09934-y
  3. Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury vol.10, pp.1, 2021, https://doi.org/10.3390/cells10010073
  4. A Two-Stage Process for Differentiation of Wharton’s Jelly-Derived Mesenchymal Stem Cells into Neuronal-like Cells vol.2021, 2019, https://doi.org/10.1155/2021/6631651
  5. Perspectives in the Cell-Based Therapies of Various Aspects of the Spinal Cord Injury-Associated Pathologies: Lessons from the Animal Models vol.10, pp.11, 2019, https://doi.org/10.3390/cells10112995
  6. Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury vol.22, pp.24, 2021, https://doi.org/10.3390/ijms222413672