본문 바로가기
KERD
논문KCI 등재

The mechanism of human neural stem cell secretomes improves neuropathic pain and locomotor function in spinal cord injury rat models: through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

초록

Background: Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%–69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)- secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities. Methods: A proper experimental study investigated 15 Rattus norvegicus divided into normal, control, and treatment groups (30 μL HNSC-secretome, intrathecal in the level of T10, three days post-traumatic SCI). Twentyeight days post-injury, specimens were collected, and matrix metalloproteinase (MMP)-9, F2-Isoprostanes, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and brain derived neurotrophic factor (BDNF) were analyzed. Locomotor recovery was evaluated via Basso, Beattie, and Bresnahan scores. Neuropathic pain was evaluated using the Rat Grimace Scale. Results: The HNSC-secretome could improve locomotor recovery and neuropathic pain, decrease F2-Isoprostane (antioxidant), decrease MMP-9 and TNF-α (anti-inflammatory), as well as modulate TGF-β and BDNF (neurotrophic factor). Moreover, HNSC-secretomes maintain the extracellular matrix of SCI by reducing the matrix degradation effect of MMP-9 and increasing the collagen formation effect of TGF-β as a resistor of glial scar formation. Conclusions: The present study demonstrated the mechanism of HNSC-secretome in improving neuropathic pain and locomotor function in SCI through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

Abstract

Background: Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%–69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)- secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities. Methods: A proper experimental study investigated 15 Rattus norvegicus divided into normal, control, and treatment groups (30 μL HNSC-secretome, intrathecal in the level of T10, three days post-traumatic SCI). Twentyeight days post-injury, specimens were collected, and matrix metalloproteinase (MMP)-9, F2-Isoprostanes, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and brain derived neurotrophic factor (BDNF) were analyzed. Locomotor recovery was evaluated via Basso, Beattie, and Bresnahan scores. Neuropathic pain was evaluated using the Rat Grimace Scale. Results: The HNSC-secretome could improve locomotor recovery and neuropathic pain, decrease F2-Isoprostane (antioxidant), decrease MMP-9 and TNF-α (anti-inflammatory), as well as modulate TGF-β and BDNF (neurotrophic factor). Moreover, HNSC-secretomes maintain the extracellular matrix of SCI by reducing the matrix degradation effect of MMP-9 and increasing the collagen formation effect of TGF-β as a resistor of glial scar formation. Conclusions: The present study demonstrated the mechanism of HNSC-secretome in improving neuropathic pain and locomotor function in SCI through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

참고문헌 (50)

  1. Kwon BK, "Neurochemical biomarkers in spinal cord injury", Spinal Cord, 57, pp.819~831 (2019)
  2. Miranpuri GS, "Folic acid modulates matrix metalloproteinase-9 expression following spinal cord injury", Ann Neurosci, 26, pp.60~65 (2019)
  3. Hagen EM, "Management of neuropathic pain associated with spinal cord injury", Pain Ther, 4, pp.51~65 (2015)
  4. Majid Davari, "Pregabalin and gabapentin in neuropathic pain management after spinal cord injury: a systematic review and meta-analysis", The Korean Journal of Pain, 33(1), pp.3~12 (2020), 대한통증학회[DOI]
  5. Liau LL, "Treatment of spinal cord injury with mesenchymal stem cells", Cell Biosci, 10, pp.112~ (2020)
  6. Sajad Fakhri, "Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activities", The Korean Journal of Pain, 35(3), pp.291~302 (2022), 대한통증학회[DOI]
  7. Assinck P, "Cell transplantation therapy for spinal cord injury", Nat Neurosci, 20, pp.637~647 (2017)
  8. Pajer K, "Stem cell secretome for spinal cord repair: is it more than just a random baseline set of factors?", Cells, 10, pp.3214~ (2021)
  9. Sabelström H, "Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice", Science, 342, pp.637~640 (2013)
  10. Dilogo IH, "Role of mesenchymal stem cellconditioned medium(MSC-CM)in the bone regeneration : a systematic review from 2007-2018", Annu Res Rev Biol, 31, pp.1~16 (2019)
  11. Cunningham CJ, "The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke", J Cereb Blood Flow Metab, 38, pp.1276~1292 (2018)
  12. Zhou J, "Human neural stem cell secretome inhibits lipopolysaccharide-induced neuroinflammation through modulating microglia polarization by activating peroxisome proliferator-activated receptor gamma", Stem Cells Dev, 31, pp.369~382 (2022)
  13. Aysel Mercan, "Immunological mechanism of postherpetic neuralgia and effect of pregabalin treatment on the mechanism: a prospective single-arm observational study", The Korean Journal of Pain, 34(4), pp.463~470 (2021), 대한통증학회[DOI]
  14. Gao L, "Progress in stem cell therapy for spinal cord injury", Stem Cells Int, 2020, pp.2853650~ (2020)
  15. Haider T, "The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats", Exp Neurol, 267, pp.230~242 (2015)
  16. Oliveri RS, "Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury : systematic review with meta-analyses of rat models", Neurobiol Dis, 62, pp.338~353 (2014)
  17. Swenson J, "Exotic Animal Formulary", pp.636~663 (2018), Saunders
  18. George RP, "Use of the rat grimace scale to evaluate visceral pain in a model of chemotherapy-induced mucositis", Animals (Basel), 9, pp.678~ (2019)
  19. Klune CB, "Comparing the Rat Grimace Scale and a composite behaviour score in rats", PLoS One, 14, pp.e0209467~ (2019)
  20. Basso DM, "A sensitive and reliable locomotor rating scale for open field testing in rats", J Neurotrauma, 12, pp.1~21 (1995)
  21. Maryam Borhani-Haghighi, "The Therapeutic Potential of Conditioned Medium from Human Breast Milk Stem Cells in Treating Spinal Cord Injury", Asian Spine Journal, 14(2), pp.131~138 (2020), 대한척추외과학회[DOI]
  22. Michael W. Carter, "Comparison of Mechanical Allodynia and Recovery of Locomotion and Bladder Function by Different Parameters of Low Thoracic Spinal Contusion Injury in Rats", The Korean Journal of Pain, 29(2), pp.86~95 (2016), 대한통증학회
  23. Leung V, "Real-time application of the Rat Grimace Scale as a welfare refinement in laboratory rats", Sci Rep, 6, pp.31667~ (2016)
  24. Wu J, "Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury", Pain, 157, pp.488~503 (2016)
  25. Hatch MN, "Neuropathic pain and SCI : identification and treatment strategies in the 21st century", J Neurol Sci, 384, pp.75~83 (2018)
  26. Schneider LE, "Application of the Rat Grimace Scale as a marker of supraspinal pain sensation after cervical spinal cord injury", J Neurotrauma, 34, pp.2982~2993 (2017)
  27. Cunningham CJ, "The therapeutic potential of the stem cell secretome for spinal cord repair : a systematic review and meta-analysis", OBM Neurobiol, 4, pp.080~ (2020)
  28. Mietto BS, "Neurotrauma and inflammation : CNS and PNS responses", Mediators Inflamm, 2015, pp.251204~ (2015)
  29. Bamidele Victor Owoyele, "Synergistic interaction between acetaminophen and L-carnosine improved neuropathic pain via NF-κB pathway and antioxidant properties in chronic constriction injury model", The Korean Journal of Pain, 35(3), pp.271~279 (2022), 대한통증학회[DOI]
  30. Jia Z, "Oxidative stress in spinal cord injury and antioxidant-based intervention", Spinal Cord, 50, pp.264~274 (2012)
  31. Dos Santos MF, "Oxidative-signaling in neural stem cell-mediated plasticity: implications for neurodegenerative diseases", Antioxidants (Basel), 10, pp.1088~ (2021)
  32. Giudicessi JR, "Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes", Transl Res, 161, pp.1~14 (2013)
  33. Clausen F, "Interstitial F(2)-isoprostane 8-iso-PGF(2α)as a biomarker of oxidative stress after severe human traumatic brain injury", J Neurotrauma, 29, pp.766~775 (2012)
  34. Leung L, "Cellular therapies for treating pain associated with spinal cord injury", J Transl Med, 10, pp.37~ (2012)
  35. Cheng Z, "Anti-inflammatory mechanism of neural stem cell transplantation in spinal cord injury", Int J Mol Sci, 17, pp.1380~ (2016)
  36. Li S, "The regulatory effects of transforming growth factor-β on nerve regeneration", Cell Transplant, 26, pp.381~394 (2017)
  37. Pajer K, "The mutual interaction between the host spinal cord and grafted undifferentiated stem cells fosters the production of a lesion-induced secretome", Neural Regen Res, 15, pp.1844~1845 (2020)
  38. Hansen CN, "Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice", J Neurosci, 33, pp.13101~13111 (2013)
  39. Gomes LR, "TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38MAPK and ERK1", 2 in highly invasive breast cancer cells, 2012, pp.12, 26~
  40. De Araújo AA, "Azilsartan increases levels of IL-10, down-regulates MMP-2, MMP-9, RANKL", RANK, cathepsin K and up-regulates OPG in an experimental periodontitis model, 2014, pp.9, e96750~
  41. Lakhan SE, "Matrix metalloproteinases in neuropathic pain and migraine : friends, enemies, and therapeutic targets", Pain Res Treat, 2012, pp.952906~ (2012)
  42. Anwar MA, "Inflammogenesis of secondary spinal cord injury", Front Cell Neurosci, 10, pp.98~ (2016)
  43. Joko M, "Different modifications of phosphorylated Smad3C and Smad3L through TGF-β after spinal cord injury in mice", Neurosci Lett, 549, pp.168~172 (2013)
  44. Fatemeh Shahsavari, "The ability of orexin-A to modify pain-induced cyclooxygenase-2 and brain-derived neurotrophic factor expression is associated with its ability to inhibit capsaicin-induced pulpal nociception in rats", The Korean Journal of Pain, 35(3), pp.261~270 (2022), 대한통증학회[DOI]
  45. Weishaupt N, "Synergistic effects of BDNF and rehabilitative training on recovery after cervical spinal cord injury", Behav Brain Res, 239, pp.31~42 (2013)
  46. Leech KA, "High-intensity locomotor exercise increases brain-derived neurotrophic factor in individuals with incomplete spinal cord injury", J Neurotrauma, 34, pp.1240~1248 (2017)
  47. Boyce VS, "Neurotrophins and spinal circuit function", Front Neural Circuits, 8, pp.59~ (2014)
  48. Tashiro S, "BDNF induced by treadmill training contributes to the suppression of spasticity and allodynia after spinal cord injury via upregulation of KCC2", Neurorehabil Neural Repair, 29, pp.677~689 (2015)
  49. Kusiak AN, "Neuroplasticity in the spinal cord", Handb Clin Neurol, 110, pp.23~42 (2013)
  50. Anjum A, "Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms", Int J Mol Sci, 21, pp.7533~ (2020)

관련 논문AI추천

Intrathecal administration of naringenin improves motor dysfunction and neuropathic pain following compression spinal cord injury in rats: relevance to its antioxidant and anti-inflammatory activitiesAhmad Mohammadi-Farani, Amir Kiani, Ehsan Mohammadi-Noori, Fatemeh Abbaszadeh, Khodabakhsh Rashidi, Mohammad Hosein Farzaei, Sajad Fakhri, Shahryar Sabouri대한통증학회 · The Korean Journal of Pain2022 · 제35권 제3호Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats고영권, 송창화, 이원형, ZHANGENJI대한통증학회 · The Korean Journal of Pain2014 · 제27권 제3호Human induced neural stem cells support functional recovery in spinal cord injury models유승권, Hong Wonjun, Kang Phil Jun, Kim In Yong, Lee Jang-Bo, Park Gyuman, Park Kyoungmin, Priscilla Lia, Son Daryeon, Song Gwonhwa, Yoo Jeong-Eun, Yoon Byung Sun, Zheng Jie생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 The effect of human mesenchymal stem cell injection on pain behavior in chronic post-ischemia pain mice유시현, Heecheol Jin, Hue Jung Park, Jae Hong Park, Seunghwan Lee, Seunghyeon Lee, Sung Hyun Lee대한통증학회 · The Korean Journal of Pain2020 · 제33권 제1호Functional analysis of secreted tissue inhibitor of metalloproteinases-1 from adult human neural stem cells (ahNSCs) for regeneration and neuroprotectionChung Kwon Kim, Dong Geun Hong, Dong Oh Kim, Geun-Hyoung Ha, Hye Yun Chae, Ki Hoon Kim, Kyeung Min Joo, So Heun Lee생화학분자생물학회 · BMB Reports2025 · 제58권 제10호Transplantation of human dental pulp stem cells promotes peripheral nerve regeneration after sciatic nerve injury in rats김원재, 박홍주, 성경주, 오희균, 정지연, 정현우대한구강생물학회 · International Journal of Oral Biology2024 · 제49권 제4호

이 간행물의 다른 논문 (11건)