Skip to main content

Advertisement

SpringerLink
Log in

Exosomes Derived from lncRNA TCTN2-Modified Mesenchymal Stem Cells Improve Spinal Cord Injury by miR-329-3p/IGF1R Axis

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Mesenchymal stem cells (MSCs)-derived exosomes play significant roles in alleviating spinal cord injury (SCI). Previous study showed that long non-coding RNA tectonic family member 2 (TCTN2) was able to relieve SCI. Herein, whether TCTN2 exerted its roles in functional recovery after SCI via exosomes derived from MSCs was explored. The SCI model was established in rats, and the neurological function was evaluated using the Basso, Beattie, and Bresnahan (BBB) scoring. Lipopolysaccharide (LPS)-induced differentiated PC12 cells were used as an in vitro model for neurotoxicity research. The expression of genes and proteins was detected by qRT-PCR and Western blot. Exosomes were isolated by ultracentrifugation and qualified by TEM and Western blot. In vitro assays were performed using CCK-8 assay, EdU assay, and flow cytometry, respectively. Dual-luciferase reporter assay and RIP assay were used to confirm the target relationship between miR-329-3p and TCTN2 or insulin-like growth factor1 receptor (IGF1R). TCTN2 expression was down-regulated in SCI model rat and lipopolysaccharide (LPS)-stimulated PC12 cells. MSCs produced exosomes and could package TCTN2 into secreted exosomes. Tail vein injection of TCTN2 exosomes into rats significantly improved functional recovery of SCI. Meanwhile, TCTN2 exosomes treatment alleviated LPS-induced neuronal apoptosis, inflammation, and oxidative stress in vitro. Additionally, TCTN2 targeted miR-329-3p and subsequently regulated the expression of its target IGF1R. Rescue assays suggested that miR-329-3p/IGF1R axis mediated the beneficial effects of TCTN2 exosomes on LPS-treated PC12 cells. In all, exosomes derived from TCTN2-modified MSCs could improve functional recovery of SCI in vivo and attenuate LPS-induced neuronal apoptosis, inflammation, and oxidative stress in vitro via miR-329-3p/IGF1R axis, suggesting a novel insight into the development of MSC-exosomes-based therapy for SCI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data and Materials Availability

The analyzed datasets generated during the present study are available from the corresponding author on reasonable request.

References

  • Abreu SC, Weiss DJ, Rocco PR (2016) Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases? Stem Cell ResTher 7(1):53

    Article  Google Scholar 

  • Ambrozaitis KV, Kontautas E, Spakauskas B, Vaitkaitis D (2006) Pathophysiology of acute spinal cord injury. Medicina (Kaunas, Lithuania) 42(3):255–261

    Google Scholar 

  • Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W (2017) Cell transplantation therapy for spinal cord injury. Nat Neurosci 20(5):637–647

    Article  CAS  PubMed  Google Scholar 

  • Bai G, Jiang L, Meng P, Li J, Han C, Wang Y, Wang Q (2020) LncRNA neat1 promotes regeneration after spinal cord injury by targeting miR-29b. J Mol Neurosci MN

  • Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21

    Article  CAS  PubMed  Google Scholar 

  • Camussi G, Deregibus MC, Tetta C (2010) Paracrine/endocrine mechanism of stem cells on kidney repair: role of microvesicle-mediated transfer of genetic information. Curr Opin Nephrol Hypertens 19(1):7–12

    Article  CAS  PubMed  Google Scholar 

  • Chang CK, Chou W, Lin HJ, Huang YC, Tang LY, Lin MT, Chang CP (2014) Exercise preconditioning protects against spinal cord injury in rats by upregulating neuronal and astroglial heat shock protein 72. Int J Mol Sci 15(10):19018–19036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen S, Wang J (2019) HAND2-AS1 inhibits invasion and metastasis of cervical cancer cells via microRNA-330-5p-mediated LDOC1. Cancer Cell Int 19:353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Lin Y, Jia Y, Xu T, Wu F, Jin Y (2019) LncRNA HAND2-AS1 exerts anti-oncogenic effects on ovarian cancer via restoration of BCL2L11 as a sponge of microRNA-340-5p. J Cell Physiol 234(12):23421–23436

    Article  CAS  PubMed  Google Scholar 

  • Cui M, Ma X, Sun J, He J, Shen L, Li F (2017) Effects of STAT3 inhibitors on neural functional recovery after spinal cord injury in rats. Biosci Trends 10(6):460–466

    Article  PubMed  Google Scholar 

  • Dupraz S, Grassi D, Karnas D, Nieto Guil AF, Hicks D, Quiroga S (2013) The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons. PloS One 8(1):e54462

  • Fakhoury M (2015) Spinal cord injury: overview of experimental approaches used to restore locomotor activity. Rev Neurosci 26(4):397–405

    Article  PubMed  Google Scholar 

  • Greene LA, Aletta JM, Rukenstein A, Green SH (1987) PC12 pheochromocytoma cells: culture, nerve growth factor treatment, and experimental exploitation. Methods Enzymol 147:207–216

    Article  CAS  PubMed  Google Scholar 

  • Hessvik NP, Llorente A (2018) Current knowledge on exosome biogenesis and release. Cell Mol Life Sci CMLS 75(2):193–208

    Article  CAS  PubMed  Google Scholar 

  • Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7(5):393–395

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Wu D, He X, Zhao H, He Z, Lin J, Wang K, Wang W, Pan Z, Lin H et al (2019) circGSK3β promotes metastasis in esophageal squamous cell carcinoma by augmenting β-catenin signaling. Mol Cancer 18(1):160

    Article  PubMed  PubMed Central  Google Scholar 

  • Hwang DH, Park HH, Shin HY, Cui Y, Kim BG (2018) Insulin-like growth factor-1 receptor dictates beneficial effects of treadmill training by regulating survival and migration of neural stem cell grafts in the injured spinal cord. Exp Neurobiol 27(6):489–507

    Article  PubMed  PubMed Central  Google Scholar 

  • Katsuda T, Kosaka N, Takeshita F, Ochiya T (2013) The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics 13(10–11):1637–1653

    Article  CAS  PubMed  Google Scholar 

  • Kosaka N, Yoshioka Y, Fujita Y, Ochiya T (2016) Versatile roles of extracellular vesicles in cancer. J Clin Investig 126(4):1163–1172

    Article  PubMed  PubMed Central  Google Scholar 

  • Li P, Li Y, Dai Y, Wang B, Li L, Jiang B, Wu P, Xu J (2020) The LncRNA H19/miR-1-3p/CCL2 axis modulates lipopolysaccharide (LPS) stimulation-induced normal human astrocyte proliferation and activation. Cytokine 131:155106

  • Liu L, Jin X, Hu CF, Li R, Zhou Z, Shen CX (2017) Exosomes derived from mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 43(1):52–68

    Article  CAS  Google Scholar 

  • Liu Y, Zou R, Wang Z, Wen C, Zhang F, Lin F (2018) Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem J 475(22):3629–3638

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Wang Y, Gong F, Rong Y, Luo Y, Tang P, Zhou Z, Zhou Z, Xu T, Jiang T et al (2019) Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of a1 neurotoxic reactive astrocytes. J Neurotrauma 36(3):469–484

    Article  PubMed  Google Scholar 

  • Lou G, Chen Z, Zheng M, Liu Y (2017) Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med 49(6):e346

  • Lugea A, Waldron RT (2017) Exosome-mediated intercellular communication between stellate cells and cancer cells in pancreatic ductal adenocarcinoma. Pancreas 46(1):1–4

    Article  PubMed  PubMed Central  Google Scholar 

  • Martin-Rendon E, Sweeney D, Lu F, Girdlestone J, Navarrete C, Watt SM (2008) 5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies. Vox Sang 95(2):137–148

    Article  CAS  PubMed  Google Scholar 

  • Meldolesi J (2018) Exosomes and ectosomes in intercellular communication. Curr Biol CB 28(8):R435-r444

    Article  CAS  PubMed  Google Scholar 

  • Mendt M, Rezvani K, Shpall E (2019) Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant 54(Suppl 2):789–792

    Article  PubMed  Google Scholar 

  • Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM (2015) Exosome mediated communication within the tumor microenvironment. J Control Release Official J Control Release Soc 219:278–294

    Article  CAS  Google Scholar 

  • Mothe AJ, Tator CH (2012) Advances in stem cell therapy for spinal cord injury. J Clin Investig 122(11):3824–3834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakao Y, Otani H, Yamamura T, Hattori R, Osako M, Imamura H (2001) Insulin-like growth factor 1 prevents neuronal cell death and paraplegia in the rabbit model of spinal cord ischemia. J Thorac Cardiovasc Surg 122(1):136–143

    Article  CAS  PubMed  Google Scholar 

  • Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells (Dayton, Ohio) 25(11):2896–2902

    Article  Google Scholar 

  • Popovich PG (2014) Neuroimmunology of traumatic spinal cord injury: a brief history and overview. Exp Neurol 258:1–4

    Article  PubMed  Google Scholar 

  • Ren XD, Wan CX, Niu YL (2019) Overexpression of lncRNA TCTN2 protects neurons from apoptosis by enhancing cell autophagy in spinal cord injury. FEBS Open Bio 9(7):1223–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren Z, Qi Y, Sun S, Tao Y, Shi R (2020) Mesenchymal stem cell-derived exosomes: hope for spinal cord injury repair. Stem Cells Dev 29(23):1467–1478

    Article  CAS  PubMed  Google Scholar 

  • Riedemann J, Macaulay VM (2006) IGF1R signalling and its inhibition. Endocr Relat Cancer 13(Suppl 1):S33-43

    Article  CAS  PubMed  Google Scholar 

  • Roma-Rodrigues C, Fernandes AR, Baptista PV (2014) Exosome in tumour microenvironment: overview of the crosstalk between normal and cancer cells. BioMed Res Int 2014:179486

  • Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM (2017) Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 6(12):2173–2185

    Article  PubMed  PubMed Central  Google Scholar 

  • Shang Z, Ou T, Xu J, Yan H, Cui B, Wang Q, Wu J, Jia C, Cui X, Li J (2020) MicroRNA expression profile in the spinal cord injured rat neurogenic bladder by next-generation sequencing. Transl Androl Urol 9(4):1585–1602

    Article  PubMed  PubMed Central  Google Scholar 

  • Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156

    Article  CAS  PubMed  Google Scholar 

  • Su Y, Liu Y, Ma C, Guan C, Ma X, Meng S (2021) Mesenchymal stem cell-originated exosomal lncRNA HAND2-AS1 impairs rheumatoid arthritis fibroblast-like synoviocyte activation through miR-143-3p/TNFAIP3/NF-κB pathway. J Orthop Surg Res 16(1):116

    Article  PubMed  PubMed Central  Google Scholar 

  • Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ (2017) Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics 7(1):180–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Lu X, Zhu R, Zhang K, Li S, Chen Z, Li L (2017) Betulinic acid induces apoptosis in differentiated PC12 cells via ROS-mediated mitochondrial pathway. Neurochem Res 42(4):1130–1140

    Article  CAS  PubMed  Google Scholar 

  • Witiw CD, Fehlings MG (2015) Acute Spinal Cord Injury. J Spinal Disord Tech 28(6):202–210

    Article  Google Scholar 

  • Zhang H, Li D, Zhang Y, Li J, Ma S, Zhang J, Xiong Y, Wang W, Li N, Xia L (2018) Knockdown of lncRNA BDNF-AS suppresses neuronal cell apoptosis via downregulating miR-130b-5p target gene PRDM5 in acute spinal cord injury. RNA Biol 15(8):1071–1080

    PubMed  PubMed Central  Google Scholar 

  • Zhao XM, He XY, Liu J, Xu Y, Xu FF, Tan YX, Zhang ZB, Wang TH (2019) Neural stem cell transplantation improves locomotor function in spinal cord transection rats associated with nerve regeneration and IGF-1 R expression. Cell Transpl 28(9–10):1197–1211

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou R, Chen KK, Zhang J, Xiao B, Huang Z, Ju C, Sun J, Zhang F, Lv XB, Huang G (2018) The decade of exosomal long RNA species: an emerging cancer antagonist. Mol Cancer 17(1):75

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Spine Surgery, Hainan General Hospital, Haikou, Hainan, China

    Jian Liu & Mingxia Lin

  2. Jinan University, Guangzhou, China

    Jian Liu

  3. Department of laboratory, The Fifth People Hospital of Hainan Province, No 49, Longkun South Road, Haikou, 570206, Hainan, China

    Feng Qiao

  4. Department of Endoscopy, Jilin Cancer Hospital, Changchun, Jilin, China

    Chenghua Zhang

Authors
  1. Jian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingxia Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chenghua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and methodology: Mingxia Lin and Feng Qiao; formal analysis and data curation: Feng Qiao and Chenghua Zhang; validation and investigation: Jian Liu and Feng Qiao; writing-original draft preparation and writing-review and editing: Jian Liu, Mingxia Lin, and Feng Qiao; approval of final manuscript: all authors.

Corresponding author

Correspondence to Feng Qiao.

Ethics declarations

Ethics Approval and Consent to Participate

The present study was approved by the ethical review committee of Hainan General Hospital with grant No. 20190628. Written informed consent was obtained from all enrolled patients.

Patient Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlight

• TCTN2 is down-regulated in SCI model rat and LPS-stimulated PC12 cells

• MSCs packages TCTN2 into secreted exosomes

• TCTN2 exosomes improve functional recovery after SCI in vivo

• TCTN2 exosomes suppress neuronal apoptosis, inflammation, and oxidative stress in vitro

• TCTN2 exosomes exert its neuroprotective effects via miR-329-3p/IGF1R axis

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 143 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Lin, M., Qiao, F. et al. Exosomes Derived from lncRNA TCTN2-Modified Mesenchymal Stem Cells Improve Spinal Cord Injury by miR-329-3p/IGF1R Axis. J Mol Neurosci 72, 482–495 (2022). https://doi.org/10.1007/s12031-021-01914-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-021-01914-7

Keywords

Search

Navigation