Use of Allogeneic Hypoxic Mesenchymal Stem Cells For Treating Disc Degeneration in Rabbits

Abstract

Intervertebral discs (IVDs) are important biomechanical components of the spine. Once degenerated, mesenchymal stem cell (MSC)‐based therapies may aid in the repair of these discs. Although hypoxic preconditioning enhances the chondrogenic potential of MSCs, it is unknown whether bone marrow MSCs expanded under hypoxic conditions (1% O2, here referred to as hypoxic MSCs) are better than bone marrow MSCs expanded under normoxic conditions (air, here referred to as normoxic MSCs) with regards to disc regeneration capacity. The purpose of this study was to compare the therapeutic effects of hypoxic and normoxic MSCs in a rabbit needle puncture degenerated disc model after intra‐disc injection. Six weeks after needle puncture, MSCs were injected into the IVD. A vehicle‐treated group and an un‐punctured sham‐control group were included as controls. The tissues were analyzed by histological and immunohistochemical methods 6 and 12 weeks post‐injection. At 6 and 12 weeks, less disc space narrowing was evident in the hypoxic MSC‐treated group compared to the normoxic MSC‐treated group. Significantly better histological scores were observed in the hypoxic MSC group. Discs treated with hypoxic MSCs also demonstrated significantly better extracellular matrix deposition in type II and XI collagen. Increased CD105 and BMP‐7 expression were also observed upon injection of hypoxic MSCs. In conclusion, hypoxic MSC injection was more effective than normoxic MSC injection for reducing IVD degeneration progression in vivo. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1440–1450, 2019.

Improving Cell Therapy Survival and Anabolism in Harsh Musculoskeletal Disease Environments

“…For the disc, two studies investigated the use of hypoxic preculture before cell implantation and demonstrated decreased loss of disc height, improved matrix protein expression, and improved cell survival. 106,107 One study investigated mechanical loading in a hydrogel system with TGFb1 present before cell implantation and demonstrated improved GAG deposition and SOX9 and collagen II expression. 108 In addition, selection of cells highly expressing TGFb1 and TGFb2 receptors before implantation demonstrated improved tissue morphology while increasing anabolic gene expression.…”

Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases

“…To retard the process IVD degeneration or maintain the structure as well as the function of degenerative discs, different rabbit models of disc degeneration have been used with applications of autologous, allogeneic or human derived stem cells as well as chondrocytes with or without genetic modification of the cells or in combination with bioscaffolds 68–82 (Table 4). Bone marrow-derived MSCs, synovial MSCs, umbilical cord tissue-derived MSCs, adipose-derived stem cells (ADSCs), and embryonic stem cells (ESCs) have been used with or without in vitro differentiation toward a chondrocyte lineage.…”

“…Bone marrow-derived MSCs, synovial MSCs, umbilical cord tissue-derived MSCs, adipose-derived stem cells (ADSCs), and embryonic stem cells (ESCs) have been used with or without in vitro differentiation toward a chondrocyte lineage. 68–78 The regenerative effect of bone morphogenic protein 2 (BMP2), which is known to have biological effects on the differentiation of MSCs into chondrocyte-like cells in platelet-rich plasma (PRP) gel culture, was investigated in a rabbit model of disc degeneration. Autologous bone marrow-derived MSCs transduced with AdV vectors encoding for BMP2 (AdV-BMP2) and loaded in PRP gel (MSC-AdV-BMP2-PRP; 1 × 10 6 cells/20 µL) were directly injected into anular-punctured lumbar discs.…”

Biomaterials-Induced Stem Cells Specific Differentiation Into Intervertebral Disc Lineage Cells

“…Several favorable results have been observed for stem cell therapy of IVDD. Though transplanted mesenchymal stem cells (MSCs) can differentiate into intervertebral disc (IVD) cells and significantly promote extracellular matrix (ECM) synthesis in IVD tissues (Chiang et al, 2019) and improve clinical outcome (Noriega et al, 2017) of IVDD patients as well, there were unexpected findings obtained in some studies. An aggravation of IVDD was reported after the injection of MSCs into NP tissues because of the formation of osteophytes (Vadala et al, 2012).…”