Korean Journal of Clinical Laboratory Science (대한임상검사과학회지)

Korean Society for Clinical Laboratory Science (대한임상검사과학회)
권호 표지
DOI QR코드

DOI QR Code

Transplantation of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Improves Lower Urinary Tract Symptoms in a Rat Model

뇌유래신경영양인자 발현 중간엽 줄기세포의 하부요로증상 개선 효과

  • Jeon, Seung Hwan (Department of Urology, College of Medicine, The Catholic University of Korea) ;
  • Park, Mi-Young (Department of Clinical Laboratory Science, Suwon Science College)
  • 전승환 (가톨릭대학교 성의교정 비뇨의학과) ;
  • 박미영 (수원과학대학교 임상병리과)
  • Received : 2020.11.23
  • Accepted : 2020.12.01
  • Published : 2020.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

This study aimed to explore the effects of brain-derived neurotrophic factor (BDNF), produced by engineered immortalized mesenchymal stem cells (imMSC), on lower urinary tract symptoms (LUTS) in a rat model with neurogenic bladder (NB). Forty-eight Sprague-Dawley (SD) rats were randomly divided into the following groups: Sham control, LUTS, LUTS+imMSC (treated with immortalized MSC), and LUTS+BDNF-eMSC (treated with BDNF-expressing MSC) groups. LUTS was induced by a crush injury to the major pelvic ganglion (MPG). Bladder function was tested under anesthesia, and bladder tissue strips were collected thereafter for contractility test and western blot analysis. Western blot results showed that the expression of both Angiopoietin 1 (Ang 1) and platelet-derived growth factor (PDGF) increased with MSC injection. The effect of treatment with BDNF-eMSC on LUTS was also evaluated, and the results were found to be better than those with imMSC (P<0.05). BDNF-eMSC prevented fibrosis in the bladder tissue and significantly reduced caspase-3 levels. In conclusion, high expression of BDNF in vivo resulted in recovery of bladder function and contractility, along with the inhibition of apoptosis in a rat model.

이 연구는 신경인성 방광 쥐 모델에서 줄기세포에 의해 발현된 뇌유래신경영양인자가 하부요로 증상에 미치는 영향을 조사하였다. 48마리의 Sprague-Dawley 쥐를 정상군, 하부요로증상군, 하부요로증상+imMSC군 및 하부요로증상+BDNF-eMSC군으로 무작위 선정하였다. 하부요로증상모델은 골반신경절 손상에 의해 유도되었으며 방광 기능평가는 마취 하에 실시하였고, 수축성 검사 및 웨스턴 블롯 분석을 위해 방광 조직을 절제하였다. 뇌유래신경영양인자 발현 중간엽줄기세포 치료가 하부요로증상에 미치는 영향도 평가되었으며 뇌유래신경영양인자 발현 중간엽줄기세포는 방광 조직의 섬유화를 억제하였고 Caspase-3 발현을 감소시켰다. 결론적으로, 뇌유래신경영양인자 발현 중간엽줄기세포는 하부요로증상 쥐 모델에서 세포 사멸의 억제와 함께 방광의 기능 및 수축성의 회복을 가져왔다.

Keywords

References

  1. Eveno C, Lamblin A, Mariette C, Pocard M. Sexual and urinary dysfunction after proctectomy for rectal cancer. J Visc Surg. 2010;147:e21-30. https://doi.org/10.1016/j.jviscsurg.2010.02.001
  2. Hamid R, Averbeck MA, Chiang H, Garcia A, Al Mousa RT, Oh SJ, et al. Epidemiology and pathophysiology of neurogenic bladder after spinal cord injury. World J Urol. 2018;36:1517-1527. https://doi.org/10.1007/s00345-018-2301-z
  3. Atala A. Reconstitution of experimental neurogenic bladder dysfunction using skeletal muscle-derived multipotent stem cells. J Urol. 2011;185:353. https://doi.org/10.1016/S0022-5347(11)60069-4
  4. Fandel TM, Albersen M, Lin G, Qiu X, Ning H, Banie L, et al. Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury. Eur Urol. 2012;61:201-210. https://doi.org/10.1016/j.eururo.2011.07.061
  5. Gong M, Bi Y, Jiang W, Zhang Y, Chen L, Hou N, et al. Immortalized mesenchymal stem cells: an alternative to primary mesenchymal stem cells in neuronal differentiation and neuroregeneration associated studies. J Biomed Sci. 2011;18:87. https://doi.org/10.1186/1423-0127-18-87
  6. Jeon SH, Shrestha KR, Kim RY, Jung AR, Park YH, Kwon O, et al. Combination therapy using human adipose-derived stem cells on the cavernous nerve and low-energy shockwaves on the corpus cavernosum in a rat model of post-prostatectomy erectile dysfunction. Urology. 2016;88:226.e1-9. https://doi.org/10.1016/j.urology.2015.10.021
  7. Jeon SH, Zhu GQ, Bae WJ, Choi SW, Jeong HC, Cho HJ, et al. Engineered mesenchymal stem cells expressing stromal cell-derived factor-1 improve erectile dysfunction in streptozotocin-induced diabetic rats. Int J Mol Sci. 2018;19. https://doi.org/10.3390/ijms19123730
  8. Matthes SM, Reimers K, Janssen I, Liebsch C, Kocsis JD, Vogt PM, et al. Intravenous transplantation of mesenchymal stromal cells to enhance peripheral nerve regeneration. Biomed Res Int. 2013; 2013:573169. https://doi.org/10.1155/2013/573169
  9. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003;9:702-712. https://doi.org/10.1038/nm0603-702
  10. Zhu GQ, Jeon SH, Lee KW, Cho HJ, Ha US, Hong SH, et al. Engineered stem cells improve neurogenic bladder by over-expressing SDF-1 in a pelvic nerve injury rat model. Cell Transplant. 2020;29:963689720902466. https://doi.org/10.1177/0963689720902466
  11. Liu TM, Ng WM, Tan HS, Vinitha D, Yang Z, Fan JB, et al. Molecular basis of immortalization of human mesenchymal stem cells by combination of p53 knockdown and human telomerase reverse transcriptase overexpression. Stem Cells Dev. 2013;22: 268-278. https://doi.org/10.1089/scd.2012.0222
  12. Kim DH, Zhao X. BDNF protects neurons following injury by modulation of caspase activity. Neurocrit Care. 2005;3:71-76. https://doi.org/10.1385/NCC:3:1:071
  13. Nelson KR, Stevens SM, McLoon LK. Prolongation of relaxation time in extraocular muscles with brain derived neurotrophic factor in adult rabbit. Invest Ophthalmol Vis Sci. 2016;57:5834-5842. https://doi.org/10.1167/iovs.16-19679
  14. Willoughby CL, Fleuriet J, Walton MM, Mustari MJ, McLoon LK. Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates. Invest Ophthalmol Vis Sci. 2015;56:3467-3483. https://doi.org/10.1167/iovs.15-16852
  15. Pelegri NG, Gorrie CA, Santos J. Rat hippocampal neural stem cell modulation using PDGF, VEGF, PDGF/VEGF, and BDNF. Stem Cells Int. 2019;2019:4978917. https://doi.org/10.1155/2019/4978917
  16. Yiou R, Hamidou L, Birebent B, Bitari D, Lecorvoisier P, Contremoulins I, et al. Safety of intracavernous bone marrow-mononuclear cells for postradical prostatectomy erectile dysfunction: An open dose-escalation pilot study. Eur Urol. 2016;69:988-991. https://doi.org/10.1016/j.eururo.2015.09.026
  17. Hoen L, Ecclestone H, Blok BFM, Karsenty G, Phe V, Bossier R, et al. Long-term effectiveness and complication rates of bladder augmentation in patients with neurogenic bladder dysfunction: a systematic review. Neurourol Urodyn. 2017;36:1685-1702. https://doi.org/10.1002/nau.23205
  18. Wein AJ. Long-term effectiveness and complication rates of bladder augmentation in patients with neurogenic bladder dysfunction: A systematic review. J Urol. 2019;201:38-39. https://doi.org/10.1097/01.ju.0000550215.07396.8e
  19. Rabie MA, Abd El Fattah MA, Nassar NN, El-Abhar HS, Abdallah DM. Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-kappaB axis. Biochem Pharmacol. 2018;151:126-134. https://doi.org/10.1016/j.bcp.2018.01.047
  20. Kutlu O, Yalcinkaya M, Kutlu S, Elpek GO, Koksal IT, Kukul E. Effect of doxazosin on expression of eNOS in rat kidney in the presence of partial bladder outlet obstruction. J Nephrol. 2012; 25:750-754. https://doi.org/10.5301/jn.5000055
  21. Kim SO, Song SH, Hwang EC, Park KS, Kwon DD, Ahn KY, et al. The expression of AQP1 and eNOS in menopausal rat urinary bladder. Int Neurourol J. 2010;14:78-85. https://doi.org/10.5213/inj.2010.14.2.78
  22. Leiria LO, Sollon C, Bau FR, Monica FZ, D'Ancona CL, De Nucci G, et al. Insulin relaxes bladder via PI3K/AKT/eNOS pathway activation in mucosa: unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder. J Physiol. 2013;591:2259-2273. https://doi.org/10.1113/jphysiol.2013.251843