Bone Marrow Mesenchymal Stem Cells Combined with Ultra-Purified Alginate Gel As a Regenerative Therapeutic Strategy after Discectomy for Degenerated Intervertebral Discs

Abstract

Background: Because the regenerative ability of intervertebral discs (IVDs) is restricted, defects caused by discectomy may induce insufficient tissue repair leading to further IVD degeneration. An acellular bioresorbable biomaterial based on ultra-purified alginate (UPAL) gel was developed to fill the IVD cavity and prevent IVD degeneration. However, an acellular matrix-based strategy may have limitations particularly in the elderly population, who exhibit low ability of self-repair. Therefore, further translational studies involving product combinations, such as UPAL gel plus bone marrow-derived mesenchymal stem cells (BMSCs), are required to evaluate the regenerative effects of BMSCs embedded in UPAL gel on degenerated IVDs. Methods: Rabbit BMSCs and nucleus pulposus cells (NPCs) were co-cultured in a three-dimensional (3D) system in UPAL gel. In addition, rabbit or human BMSCs combined with UPAL gel were implanted into IVDs following discectomy in rabbits with degenerated IVDs. Findings: Gene expression of NPC markers, growth factors, and extra cellular matrix was significantly increased in the NPC and BMSCs 3D co-culture compared to that in each 3D mono-culture. In vivo, whereas UPAL gel alone suppressed IVD degeneration as compared to discectomy, the combination of BMSCs and UPAL gel exerted a more potent effect to induce IVD regeneration. Similar IVD regeneration was observed using human BMSCs. Interpretation: These findings demonstrate the therapeutic potential of BMSCs combined with UPAL gel as a regenerative strategy following discectomy for degenerated IVDs. Funding Statement: This work was supported by a Grant-in-Aid for the Ministry of Education, Culture, Sports, Science, and Technology of Japan (16H03176), Japan, a “Project of Translational and Clinical Research Core Centers” from the Japan Agency for Medical Research and Development, AMED (18lm0203045h0001), Japan, and Mochida Pharmaceutical Co., Ltd Declaration of Interests: Patents pertaining to this work have been filed (inventors H. S., T. T., and N. I.). The other authors declare that they have no competing interests. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee at Hokkaido University (approval number: 13-0051) and performed in accordance with the approved guidelines.