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

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.

Enzymatic chemonucleolysis for lumbar disc herniation—an assessment of historical and contemporary efficacy and safety: a systematic review and meta-analysis

“…In addition, there is very little literature reporting long-term imaging evaluations of discs treated with chemonucleolysis (Supplemental item 4 ), and long-term clinical outcomes and more objective assessments remain largely undetermined 88 . Therefore, future work may consider revising the enzymatic destruction of herniated disc tissue through supplementation with regenerative treatments 16 , 89 , 90 e.g., co-injection of cells 91 , 92 , biomaterials 93 , 94 , extracellular vesicles 95 , 96 , or platelet-rich plasma (PRP) 97 to support the restoration of the disc over time, particularly regarding younger patients 16 , 79 . For example, previous animal studies have shown the capacity of PRP products to reverse condoliase-mediated disc deterioration 98 .…”

A comprehensive review of cell transplantation and platelet‐rich plasma therapy for the treatment of disc degeneration‐related back and neck pain: A systematic evidence‐based analysis

“…As such, further research is needed to confirm these observations. Additionally, cell and PRP injections were most commonly applied intradiscally, despite the additional damage caused by the required disc puncture, which has been shown to promote disc degeneration 4,81 . Alternative strategies, such as epidural and intraosseous transplantation, have also been successfully applied in some of the reviewed trials and might provide interesting venues for further research.…”

“…It entails the introduction of de novo cells that replace, complement, or provide a new capacity to the endemic population in the body. The transplanted cells can thereby integrate in situ and support tissue production or general homeostasis or, alternatively, may involve a temporal presence targeted at directing, activating, or attracting native cells 4 . As such, the application of (stem) cells as a means of therapy poses a potential paradigm shift in medicine.…”

Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain

“…Additional strategies for AF and endplate repair, or combined approaches, will likely be beneficial for specific LBP conditions and warrants further investigation [101] . Similarly, alternative strategies to intradiscal injection that could introduce the beneficial (effects of) cells into the disc can potentially reduce the dependency on the deteriorated IVD integrity [ 23 , 102 ].…”

“…In general, cellular therapy is well-established in the form of bone marrow transplantation for leukemia patients [18] , however, its employment for other pathologies and applications has only recently evolved into clinically approved products [19] . Cell therapy for the IVD has first been reported in 1994 [16] and has since been shown incredibly effective as a regenerative product in multiple animal studies [20] , [21] , [22] , [23] . As presented in the excellent review of Williams et al.…”