Rahul Ghosh

Introduction: Low-back pain, commonly associated with age-related degenerative disc disease (DDD), is a major healthcare burden in the United States with an estimated 60% – 90% lifetime prevalence ¹. Spinal fusion is the standard of treatment for advanced stages of DDD that are unresponsive to physical therapy or analgesics ^2,3,4. While almost 650,000 spinal fusion procedures are performed per year in the U.S., they have a failure rate of 15 – 40% ². Autologous bone grafts are currently the gold-standard, however there are risks of donor site morbidity, as well as variability in quality and supply ^2,3. Consequently, the utilization of mesenchymal stromal cells (MSCs), which also have intrinsic immunosuppressive activity, is a promising avenue for improving the availability and performance of spinal fusion grafts ^2,3,5.   Methods: MSCs were isolated from bone marrow and cultured with various materials and growth signals. Markers indicating differentiation towards the osteoblast lineage, namely alkaline phosphatase (ALP) expression and bone matrix deposition were measured ^2,5,6,7. In one study, whole transcriptome analysis was used to determine the scope of pathways were upregulated upon exposure to 2D-nanosilicates ⁷. In some studies, a rat model was used for spinal fusion surgery, and efficacy of fusion was measured through manual palpation and measurement of mechanical properties ^2,5,7.   Results: A combination of scaffolds & growth signals can be used to direct MSC differentiation in spinal fusion constructs through stimulation of differentiation pathways, including the canonical Wingless (cWnt) signaling pathways, BMP, and TGF-β mediated signaling pathways, which eventually converge on the activation of RunX2, a critical transcription factor for osteoblast differentiation ^2,5,9. Some of these constructs were implemented in a rat model of spinal fusion, demonstrating that stimulation of the cWnt and BMP pathways could be translated into improved fusion outcomes ^2,5,7.  At least two studies have determined the performance of MSC constructs to be non-inferior to autograft in a rat model of spinal fusion ^5,7.  Conclusions: While several strategies have been explored to induce MSCs into osteoblasts for functional spinal fusion constructs, further elucidation and mapping of activated pathways to specific interventions would better inform subsequent studies. Additionally, the impact of cross-talk between cWnt, TGF-β, and other differentiation pathways could be further explored to determine whether it is a net driver or inhibitor of MSC differentiation. Furthermore, evaluation of safety profile of these interventions, as well as manufacturability meeting cGMP compliance standards will be necessary to move product into clinical trials.

1. Fernandez-Moure J, Moore CA, Kim K, et al. Novel therapeutic strategies for degenerative disc disease: Review of cell biology and intervertebral disc cell therapy. SAGE Open Med. 2018;6. doi:1177/2050312118761674
2. Clough Bret H., Zeitouni Suzanne, Krause Ulf, et al. Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen‐Synthease‐Kinase‐3‐Beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo. STEM CELLS Translational Medicine. 2018;7(4):342-353. doi:1002/sctm.17-0229
3. Sakai D, Schol J. Cell therapy for intervertebral disc repair: Clinical perspective. J Orthop Translat. 2017;9:8-18. doi:1016/j.jot.2017.02.002
4. Salamanna F, Sartori M, Brodano GB, et al. Mesenchymal Stem Cells for the Treatment of Spinal Arthrodesis: From Preclinical Research to Clinical Scenario. Stem Cells Int. 2017;2017:3537094. doi:1155/2017/3537094
5. Clough BH, McNeill EP, Palmer D, et al. An allograft generated from adult stem cells and their secreted products efficiently fuses vertebrae in immunocompromised athymic rats and inhibits local immune responses. Spine J. 2017;17(3):418-430. doi:1016/j.spinees.2016.10.009
6. Banik BL, Riley TR, Platt CJ, Brown JL. Human Mesenchymal Stem Cell Morphology and Migration on Microtextured Titanium. Front Bioeng Biotechnol. 2016;4. doi:3389/fbioe.2016.00041
7. Wu M, Chen G, Li Y-P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. doi:1038/boneres.2016.9
8. Gu Y, Chen L, Niu H-Y, Shen X-F, Yang H-L. Promoting spinal fusions by biomineralized silk fibroin films seeded with bone marrow stromal cells: An in vivo animal study. J Biomater Appl. 2016;30(8):1251-1260. doi:1177/0885328215620067
9. Carrow JK, Cross LM, Reese RW, et al. Widespread changes in transcriptome profile of human mesenchymal stem cells induced by two-dimensional nanosilicates. PNAS. April 2018:201716164. doi:1073/pnas.1716164115