Homing of vertebral-delivered mesenchymal stromal cells for degenerative intervertebral discs repair - an in vivo proof-of-concept study

Jordy Schol; Daisuke Sakai; Takayuki Warita; Tadashi Nukaga; Kosuke Sako; Sebastian Wangler; Shota Tamagawa; Stephan Zeiter; Mauro Alini; Sibylle Grad

doi:10.1002/jsp2.1228

Homing of vertebral-delivered mesenchymal stromal cells for degenerative intervertebral discs repair - an in vivo proof-of-concept study

JOR Spine. 2022 Nov 14;6(1):e1228. doi: 10.1002/jsp2.1228. eCollection 2023 Mar.

Authors

Jordy Schol^{1

2}, Daisuke Sakai¹, Takayuki Warita^{2

3}, Tadashi Nukaga¹, Kosuke Sako¹, Sebastian Wangler^{4

5}, Shota Tamagawa^{1

6}, Stephan Zeiter⁴, Mauro Alini⁴, Sibylle Grad^{4

7}

Affiliations

¹ Department of Orthopaedic Surgery Tokai University School of Medicine Isehara Japan.
² Research Center for Regenerative Medicine Tokai University School of Medicine Isehara Japan.
³ TUNZ Pharma Co. Ltd. Osaka Japan.
⁴ AO Research Institute Davos Davos Switzerland.
⁵ Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital University of Bern Bern Switzerland.
⁶ Department of Medicine for Orthopaedics and Motor Organ Juntendo University Graduate School of Medicine Tokyo Japan.
⁷ ETH Zürich, Institute for Biomechanics Zürich Switzerland.

Abstract

Introduction: Cell transplantation shows promising results for intervertebral disc (IVD) repair, however, contemporary strategies present concerns regarding needle puncture damage, cell retention, and straining the limited nutrient availability. Mesenchymal stromal cell (MSC) homing is a natural mechanism of long-distance cellular migration to sites of damage and regeneration. Previous ex vivo studies have confirmed the potential of MSC to migrate over the endplate and enhance IVD-matrix production. In this study, we aimed to exploit this mechanism to engender IVD repair in a rat disc degeneration model.

Methods: Female Sprague Dawley rats were subjected to coccygeal disc degeneration through nucleus pulposus (NP) aspiration. In part 1; MSC or saline was transplanted into the vertebrae neighboring healthy or degenerative IVD subjected to irradiation or left untouched, and the ability to maintain the IVD integrity for 2 and 4 weeks was assessed by disc height index (DHI) and histology. For part 2, ubiquitously GFP expressing MSC were transplanted either intradiscally or vertebrally, and regenerative outcomes were compared at days 1, 5, and 14 post-transplantation. Moreover, the homing potential from vertebrae to IVD of the GFP⁺ MSC was assessed through cryosection mediated immunohistochemistry.

Results: Part 1 of the study revealed significantly improved maintenance of DHI for IVD vertebrally receiving MSC. Moreover, histological observations revealed a trend of IVD integrity maintenance. Part 2 of the study highlighted the enhanced DHI and matrix integrity for discs receiving MSC vertebrally compared with intradiscal injection. Moreover, GFP rates highlighted MSC migration and integration in the IVD at similar rates as the intradiscally treated cohort.

Conclusion: Vertebrally transplanted MSC had a beneficial effect on the degenerative cascade in their neighboring IVD, and thus potentially present an alternative administration strategy. Further investigation will be needed to determine the long-term effects, elucidate the role of cellular homing versus paracrine signaling, and validate our observations on a large animal model.

Keywords: cell therapy; degeneration; homing; intervertebral disc; mesenchymal stromal cells; rat model.