MicroRNA-21-5p promotes fibrosis of spinal fibroblasts after spinal cord injury_West China Medical Journal

Authors：

HAN Bing ¹ , ZHAO Qian ² , JIANG Tao ¹ , DENG Bin ¹ , FENG Li ³ ,  LIAN Shichao ¹ ,  KONG Xiangmin ¹

1. Department of Orthopedics, Zoucheng People’s Hospital, Affiliated Hospital of Jining Medical University (Zoucheng), Zoucheng, Shandong 273500, P. R. China;
2. Department of Neurosurgery, Guizhou Provincial People’s Hospital, Guizhou University Medical College, Guiyang, Guizhou 550000, P. R. China;
3. Department of Orthopedics, Jining First People’s Hospital, Jining, Shandong 272000, P. R. China;

Corresponding author：

LIAN Shichao, Email: sina_sc@126.com; KONG Xiangmin, Email: sdzckxm@163.com

Keywords：

Spinal cord injury; microRNA; Spinal fibroblast; Fibrosis; Scratch damage; miRNA-21; Fibrotic scar

DOI：

10.7507/1002-0179.202001126

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the regulatory effect of miRNA-21-5p (miR-21) on spinal fibroblasts, and to explore the mechanism of miR-21 related pathological process of spinal cord injury.Methods Spinal cord fibroblasts were identified by immunofluorescence. Spinal fibroblasts damage model was established by scratch method. Quantitative real-time polymerase chain reaction (RT-PCR) was used to determine the relative expression of miR-21 and fibrosis-related genes in spinal cord fibroblasts after injury. The expression of miR-21 in spinal cord fibroblasts was up-regulated and down-regulated by using miR-21 mimics/inhibitor, and the expression levels of apoptosis and proliferation-related proteins were detected by Western Blot (WB).Results The expression of miR-21 and fibrosis-related genes were increased after spinal cord fibroblast scratch (P<0.05). Up-regulation of the miR-21 can increase the expression of apoptosis-related genes in fibroblasts (P<0.05), and vice versa. The proliferation of fibroblasts was consistent with the expression of miR-21, while the apoptosis of fibroblasts was contrary to the expression of miR-21.Conclusions miR-21 enhanced the fibrosis and proliferation, inhibited the apoptosis of spinal cord fibroblasts after mechanical injury. This indicates that miR-21 is closely related with the formation of fibrotic scar after spinal cord injury, which also providesa potential therapeutic target for spinal cord injury.

Citation： HAN Bing, ZHAO Qian, JIANG Tao, DENG Bin, FENG Li, LIAN Shichao, KONG Xiangmin. MicroRNA-21-5p promotes fibrosis of spinal fibroblasts after spinal cord injury. West China Medical Journal, 2020, 35(7): 845-850. doi: 10.7507/1002-0179.202001126 Copy

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11.	Zhu Y, Soderblom C, Trojanowsky M, et al. Fibronectin matrix assembly after spinal cord injury. J Neurotrauma, 2015, 32(15): 1158-1167.
12.	Dore-Duffy P, Owen C, Balabanov R, et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res, 2000, 60(1): 55-69.
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14.	Dias DO, Göritz C. Fibrotic scarring following lesions to the central nervous system. Matrix Biol, 2018, 68-69: 561-570.
15.	Vienberg S, Geiger J, Madsen S, et al. MicroRNAs in metabolism. Acta Physiol (Oxf), 2017, 219(2): 346-361.
16.	Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009, 136(2): 215-233.
17.	Yuan J, Chen H, Ge D, et al. Mir-21 promotes cardiac fibrosis after myocardial infarction via targeting Smad7. Cell Physiol Biochem, 2017, 42(6): 2207-2219.
18.	Ruschel J, Hellal F, Flynn KC, et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science, 2015, 348(6232): 347-352.
19.	Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 2006, 7(8): 617-627.
20.	Katarina O, Lucia M, Dana J, et al. Fibrotic scar model and TGF ‐β1 differently modulate action potential firing and voltage‐dependent ion currents in hippocampal neurons in primary culture. Eur J Neurosci, 2017, 46(6): 2161-2176.
21.	Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol, 2011, 3(3): 83-92.
22.	Ning B, Gao L, Liu RH, et al. microRNAs in spinal cord injury: potential roles and therapeutic implications. Int J Biol Sci, 2014, 10(9): 997-1006.
23.	Nieto-Diaz M, Esteban FJ, Reigada D, et al. MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front Cell Neurosci, 2014, 8: 53.
24.	Liu R, Wang W, Wang S, et al. microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-β signaling. Aging (Albany NY), 2018, 10(6): 1474-1488.
25.	Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature, 2008, 456(7224): 980-984.
26.	Zhang J, Jiao J, Cermelli S, et al. miR-21 inhibition reduces liver fibrosis and prevents tumor development by inducing apoptosis of CD24+progenitor cells. Cancer Res, 2015, 75(9): 1859-1867.
27.	Lorenzen JM, Schauerte C, Hübner A, et al. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur Heart J, 2015, 36(32): 2184-2196.
28.	Pandit KV, Milosevic J, Kaminski N. MicroRNAs in idiopathic pulmonary fibrosis. Translational Research, 2011, 157(4): 191-199.
29.	Chung ACK, Lan HY. MicroRNAs in renal fibrosis. Front Physiol, 2015, 6: 50.
30.	Gaur AB, Holbeck SL, Colburn NH, et al. Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro Oncol, 2011, 13(6): 580-590.

1. Lang BT, Cregg JM, DePaul MA, et al. Modulation of the proteoglycan receptor PTP σpromotes recovery after spinal cord injury. Nature, 2015, 518(7539): 404-408.
2. Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers, 2017, 3: 17018.
3. Anderson MA, Burda JE, Ren Yl, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature, 2016, 532(7598): 195-200.
4. Ahuja CS, Nori S, Tetreault L, et al. Traumatic spinal cord injury-repair and regeneration. Neurosurgery, 2017, 80(3): S9-S22.
5. Zhao Z, Nelson AR, Betsholtz C, et al. Establishment and dysfunction of the blood-brain barrier. Cell, 2015, 163(5): 1064-1078.
6. Rockey DC, Bell PD, Hill JA. Fibrosis--a common pathway to organ injury and failure. N Engl J Med, 2015, 372(12): 1138-1149.
7. Heindryckx F, Li JP. Role of proteoglycans in neuro-inflammation and central nervous system fibrosis. Matrix Biol, 2018, 68-69: 589-601.
8. Zhu Y, Soderblom C, Krishnan V, et al. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis, 2015, 74: 114-125.
9. O’Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest, 2017, 127(9): 3259-3270.
10. Soderblom C, Luo X, Blumenthal E, et al. Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci, 2013, 33(34): 13882-13887.
11. Zhu Y, Soderblom C, Trojanowsky M, et al. Fibronectin matrix assembly after spinal cord injury. J Neurotrauma, 2015, 32(15): 1158-1167.
12. Dore-Duffy P, Owen C, Balabanov R, et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res, 2000, 60(1): 55-69.
13. Kawano H, Kimura-Kuroda J, Komuta Y, et al. Role of the lesion scar in the response to damage and repair of the central nervous system. Cell Tissue Res, 2012, 349(1): 169-180.
14. Dias DO, Göritz C. Fibrotic scarring following lesions to the central nervous system. Matrix Biol, 2018, 68-69: 561-570.
15. Vienberg S, Geiger J, Madsen S, et al. MicroRNAs in metabolism. Acta Physiol (Oxf), 2017, 219(2): 346-361.
16. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009, 136(2): 215-233.
17. Yuan J, Chen H, Ge D, et al. Mir-21 promotes cardiac fibrosis after myocardial infarction via targeting Smad7. Cell Physiol Biochem, 2017, 42(6): 2207-2219.
18. Ruschel J, Hellal F, Flynn KC, et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science, 2015, 348(6232): 347-352.
19. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 2006, 7(8): 617-627.
20. Katarina O, Lucia M, Dana J, et al. Fibrotic scar model and TGF ‐β1 differently modulate action potential firing and voltage‐dependent ion currents in hippocampal neurons in primary culture. Eur J Neurosci, 2017, 46(6): 2161-2176.
21. Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol, 2011, 3(3): 83-92.
22. Ning B, Gao L, Liu RH, et al. microRNAs in spinal cord injury: potential roles and therapeutic implications. Int J Biol Sci, 2014, 10(9): 997-1006.
23. Nieto-Diaz M, Esteban FJ, Reigada D, et al. MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front Cell Neurosci, 2014, 8: 53.
24. Liu R, Wang W, Wang S, et al. microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-β signaling. Aging (Albany NY), 2018, 10(6): 1474-1488.
25. Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature, 2008, 456(7224): 980-984.
26. Zhang J, Jiao J, Cermelli S, et al. miR-21 inhibition reduces liver fibrosis and prevents tumor development by inducing apoptosis of CD24+progenitor cells. Cancer Res, 2015, 75(9): 1859-1867.
27. Lorenzen JM, Schauerte C, Hübner A, et al. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur Heart J, 2015, 36(32): 2184-2196.
28. Pandit KV, Milosevic J, Kaminski N. MicroRNAs in idiopathic pulmonary fibrosis. Translational Research, 2011, 157(4): 191-199.
29. Chung ACK, Lan HY. MicroRNAs in renal fibrosis. Front Physiol, 2015, 6: 50.
30. Gaur AB, Holbeck SL, Colburn NH, et al. Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro Oncol, 2011, 13(6): 580-590.

West China Medical Journal

MicroRNA-21-5p promotes fibrosis of spinal fibroblasts after spinal cord injury

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