Locally Applied Stem Cell Exosome-Scaffold Attenuates Nerve Injury-Induced Pain in Rats

Jong-Ming Hsu; Sheng-Jie Shiue; Kuender D Yang; Han-Shiang Shiue; Yi-Wei Hung; Pavani Pannuru; Raju Poongodi; Hsin-Yi Lin; Jen-Kun Cheng

doi:10.2147/JPR.S286771

Locally Applied Stem Cell Exosome-Scaffold Attenuates Nerve Injury-Induced Pain in Rats

J Pain Res. 2020 Dec 4:13:3257-3268. doi: 10.2147/JPR.S286771. eCollection 2020.

Authors

Jong-Ming Hsu^#^{1

2

3}, Sheng-Jie Shiue^#⁴, Kuender D Yang^#^{5

6

7}, Han-Shiang Shiue⁸, Yi-Wei Hung⁴, Pavani Pannuru⁴, Raju Poongodi⁴, Hsin-Yi Lin^{9

10}, Jen-Kun Cheng^{3

4

11}

Affiliations

¹ Department of Urology, Mackay Memorial Hospital, Taipei 10449, Taiwan.
² Mackay Junior College of Medicine, Nursing, and Management, Taipei 11260, Taiwan.
³ Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
⁴ Department of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan.
⁵ Institute of Biomedical Science, Mackay Medical College, New Taipei City 252, Taiwan.
⁶ Department of Pediatrics, Mackay Memorial Hospital, Taipei 10449, Taiwan.
⁷ Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
⁸ Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan.
⁹ Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 106, Taiwan.
¹⁰ Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei 106, Taiwan.
¹¹ Department of Anesthesiology, Mackay Memorial Hospital, Taipei 10449, Taiwan.

^# Contributed equally.

Abstract

Purpose: Nerve injury-induced pain is difficult to treat. In this study, we developed an alginate scaffold with human umbilical cord mesenchymal stem cell exosomes (EX-SC) to treat nerve injury-induced pain.

Materials and methods: The scaffold was prepared and characterized for its physical traits and biocompatibility. In vitro studies of PC12 and HEK293 cells were used to evaluate the neuroprotective and neurotrophic effects of exosomes. Right L5/6 spinal nerve ligation (SNL) was performed in Sprague-Dawley rats to induce mechanical allodynia and thermal hyperalgesia, evaluated by von Frey hair and radiant heat tests. The EX-SC was wrapped around ligated L5/6 spinal nerves for treatment. Western blotting and immunofluorescence staining were used to evaluate neuron/glial activation, cytokines and neurotrophic factor of affected dorsal root ganglion (DRG).

Results: In cell culture assay, the exosomes induce neurite outgrowth of PC12 cells and protect PC12 and HEK293 cells against formaldehyde acid treatment. On post-ligation day 21, rats receiving EX-SC had significantly higher median (interquartile range) withdrawal threshold and latency [14.1 (13.7-15.5) g, 14.2 (13.7-15.3) s] than saline-SC-treated rats [2.1 (1.7-3.0) g, 2.0 (1.8-2.4) s, P=0.02 and 0.002]. The EX-SC also attenuated SNL-induced up-regulation of c-Fos, GFAP, Iba1, TNF-α and IL-1β, while enhancing the level of IL-10 and GDNF, in the ipsilateral L5/6 DRG. After implantation for 21 days, the EX-SC enhanced the expression of myelin basic protein and IL-10 in injured L5/6 axons.

Conclusion: We demonstrate the EX-SC possesses antinociceptive, anti-inflammation and pro-neurotrophic effects in the SNL pain model. It could be a promising therapeutic alternative for nerve injury-induced pain.

Keywords: exosome; nerve injury; neuropathic pain; scaffold; spinal nerve ligation; stem cell.

Grants and funding

This work was supported by grants from Ministry of Science and Technology, Taiwan [MOST 105-2314-B-195-003-MY3 and 108-2314-B-195-006-MY3 (to J.K.C.); 106-2811-B-195-001 and 107-2811-B-195-500 (to S.J.S.); 108-2811-B-195-500 (to P.P.)]; Mackay Memorial Hospital, Taipei, Taiwan [MMH-E-108-15, MMH-E-109-15, MMH 10723, 10799, 107105, TT-10705, 10801 (to J.K.C.); MMH-E-107-05 (to K.D.Y.)]; and National Taipei University of Technology [NTUT-MMH Joint Research Program, NTUT-MMH-107-05, NTUT-MMH-108-01 and 108DMH0100032 (to H.Y.L.)].