Evaluation of biological therapies and diagnostic targets for the degenerative intervertebral disc (Theranostic)

Background

Intervertebral disc (IVD) degeneration is a major factor contributing to the development of back and neck pain, which represents a global burden for patients, clinicians, and the society. Application of mesenchymal stem cell (MSC) secretome is an attractive therapeutic approach, avoiding some of the hurdles and risks of cell injection.

Goal

The aim is to evaluate the potential of MSC secretome for IVD regeneration using cell and organ culture models. Composition of the secretome will be correlated to its regenerative effect to identify potent secretomes for further pre-clinical study.

Results

Stimulation of MSCs with IVD conditioned media induced a more complex MSC secretome, involving more diverse sets of upregulated biological processes, compared to stimulation with IL-1β as proinflammatory control. Furthermore, the MSCs' response to stimulation with IVD conditioned medium was dependent on the IVD's pathological status. The MSC secretome seemed to match the primary need of the IVD.

Analysis of proteomics data of released proteins following stimulation of MSCs with degenerative IVD conditioned medium. Top 5 upregulated (upper part) and downregulated (lower part) gene ontology terms (functional database: biological processes) are displayed. From: DOI: 10.1186/s13287-020-02062-2.

Publication

Li Z, Gehlen Y, Heizmann F, Grad S, Alini M, Richards RG, Kubosch D, Südkamp N, Izadpanah K, Kubosch EJ and Lang G. Preclinical ex-vivo testing of anti-inflammatory drugs in a bovine intervertebral degenerative disc model. Front. Bioeng. Biotechnol. 8:583, 2020. doi: 10.3389/fbioe.2020.00583

Du J, Pfannkuche JJ, Lang G, Creemers LB, Alini M, Grad S, Li Z. Proinflammatory intervertebral disc cell and organ culture models induced by tumor necrosis factor alpha. JOR Spine. 2020 Jun 19;3(3):e1104. doi: 10.1002/jsp2.1104. eCollection 2020 Sep.

Zhou Z, Cui S, Du J, Richards RG, Alini M, Grad S, Li Z. One strike loading organ culture model to investigate the post-traumatic disc degenerative condition. J Orthop Transl 2020.

Cui S, Zhou Z, Liu X, Richards RG, Alini M, Peng S, Liu S, Zou X, Li Z, Grad S. Identification and characterization of serum microRNAs as biomarkers for human disc degeneration: An RNA sequencing analysis. Diagnostics (Basel). 2020 Dec 8;10(12):1063. doi: 10.3390/diagnostics10121063

Karppinen J, Koivisto K, Ketola J, Haapea M, Paananen M, Herzig KH, Alini M, Lotz J, Dudli S, Samartzis D, Risteli J, Majuri ML, Alenius H, Kyllönen E, Järvinen J, Niinimäki J, Grad S. Serum biomarkers for Modic changes in patients with chronic low back pain. Eur Spine J 2021

Karppinen J, Koivisto K, Ketola J, Haapea M, Paananen M, Herzig K-H, Alini M, Lotz J, Dudli S,Samartzis D, Risteli J, Majuri M-L, Alenius H, Kyllönen E, Järvinen J, Niinimäki J, Grad S.Serum biomarkers for Modic changes in patients with chronic low back pain. Eur Spine J. 2021;epub Jan 9. https://doi.org/10.1007/s00586-020-06713-z

Wangler S, Kamali A, Wapp C, Wuertz-Kozak K, Häckel S, Fortes C, Benneker LM, Haglund L, Richards RG, Alini M, Peroglio M, Grad S. Uncovering the secretome of mesenchymal stromal cells exposed to healthy, traumatic, and degenerative intervertebral discs: a proteomic analysis. Stem Cell Res Ther. 2021;12(1):11. https://doi.org/10.1186/s13287-020-02062-2

Kamali A, Ziadlou R, Lang G, Pfannkuche J, Cui S, Li Z, Richards RG, Alini M, Grad S. Small molecule-based treatment approaches for intervertebral disc degeneration: Current options and future directions. Theranostics. 2021;11(1):27-47. https://dx.doi.org/10.7150/thno.48987

Cui S, Zhou Z, Chen X, Wei F, Richards RG, Alini M, Grad S, Li Z. Transcriptional profiling of intervertebral disc in a post-traumatic early degeneration organ culture model. JOR Spine. 2021;epub April 8:e1146. https://doi.org/10.1002/jsp2.1146Croft AS, Illien-Jünger S, Grad S, Guerrero J, Wangler S, Gantenbein B. The application of mesenchymal stromal cells and their homing capabilities to regenerate the intervertebral disc. Int J Mol Sci. 2021;22(7):3519. https://doi.org/10.3390/ijms22073519

Nüesch A. The influence of mesenchymal stromal cells secretome on nucleus pulposus cells exposed to a proinflammatory environment. 2021 ETH Zürich (Z. Li, S. Grad, S. Ferguson) - MSc ETH HST (thesis)

Russo F, Ambrosio L, Peroglio M, Guo W, Wangler S, Gewiess J, Grad S, Alini M, Papalia R, Vadalà G, Denaro V. A hyaluronan and platelet-rich plasma hydrogel for mesenchymal stem cell delivery in the intervertebral disc: An organ culture study. Int J Mol Sci. 2021;22(6):2963

Ren W, Cui S, Alini M, Grad S, Zhou Q, Li Z, Razansky D. Noninvasive multimodal fluorescence and magnetic resonance imaging of whole-organ intervertebral discs. Biomed Opt Express. 2021;12(6):3214-27. https://doi.org/10.1364/BOE.421205

Guo P, Liu X, Zhang P, He Z, Li Z, Alini M, Richards RG, Grad S, Stoddart MJ, Zhou G, Zou X, Chan D, Tian W, Chen D, Gao M, Zhou Z, Liu S. A single-cell transcriptome of mesenchymal stromal cells to fabricate bioactive hydroxyapatite materials for bone regeneration. Bioact Mater. 2021;epub Aug 11. https://doi.org/10.1016/j.bioactmat.2021.08.009

Du J, Guo W, Hackel S, Hoppe S, Garcia JP, Alini M, Tryfonidou MA, Creemers LB, Grad S, Li Z. The function of CD146 in human annulus fibrosus cells and mechanism of the regulation by TGF-beta. J Orthop Res. 2021;epub Oct 18. https://doi.org/10.1002/jor.25190

Germscheid N, Cheung JPY, Neva MH, Oner FC, Kwon BK, Valacco M, Awwad W, Sciubba DM, Lewis SJ, Rhines LD, Yoon ST, Alini M, Grad S, Fisher CG, Samartzis D. Research practices and needs among spine surgeons worldwide. Global Spine J. 2021;epub Dec 6. https://dx.doi.org/10.1177/21925682211058158

Cui S, Li W, Teixeira GQ, Neidlinger-Wilke C, Wilke H-J, Haglund L, Ouyang H, Richards RG, Grad S, Alini M, Li Z. Neoepitope fragments as biomarkers for different phenotypes of intervertebral disc degeneration. JOR Spine. 2022;epub Jul 6. https://doi.org/10.1002/jsp2.1215

Li Y-H, Wu H-L, Li Z, Li B-B, Zhu M, Chen D, Ye F-H, Yu B-S, Huang Y-C. Species variation in the cartilaginous endplate of the lumbar intervertebral disc. JOR Spine. 2022;epub Aug 25( ):e1218. https://doi.org/10.1002/jsp2.1218

Wangler S, Kamali A, Wapp C, Wuertz-Kozak K, Häckel S, Fortes C, Benneker LM, Haglund L, Richards RG, Alini M, Peroglio M, Grad S. Uncovering the secretome of mesenchymal stromal cells exposed to healthy, traumatic, and degenerative intervertebral discs: a proteomic analysis. Stem Cell Res Ther. 2021 Jan 7;12(1):11. DOI: 10.1186/s13287-020-02062-2.

Karppinen J, Koivisto K, Ketola J, Haapea M, Paananen M, Herzig KH, Alini M, Lotz J, Dudli S, Samartzis D, Risteli J, Majuri ML, Alenius H, Kyllönen E, Järvinen J, Niinimäki J, Grad S. Serum biomarkers for Modic changes in patients with chronic low back pain. Eur Spine J. 2021 Jan 9. DOI: 10.1007/s00586-020-06713-z.

Ren W, Cui S, Alini M, Grad S, Zhou Q, Li Z, Razansky D. Noninvasive multimodal fluorescence and magnetic resonance imaging of whole-organ intervertebral discs. Biomed Opt Express. 2021 May 7;12(6):3214-3227. DOI: 10.1364/BOE.421205.

The influence of mesenchymal stromal cells secretome on nucleus pulposus cells exposed to a proinflammatory environment. Andrea Nüesch MSc ETHZ. (Thesis)

Li KH, Zhu Y, Zhang PH, Alini M, Grad S, Li Z. Osteochondral explants for diarthrodial joint diseases: bridging the gap between bench and bedside. Eur Cell Mater. 2022;44:74-98. https://www.doi.org/10.22203/eCM.v044a05

Tang SN, Bonilla AF, Cahine NO, Colbath AC, Easley JT, Grad S, Haglund L, Le Maitre CL, Leung V, McCoy AM, Purmessur D, Tang SY, Zeiter S, Smith LJ. Controversies in spine research: organ culture versus in vivo models for studies of the intervertebral disc. JOR Spine. 2022;epub Nov 28:e:1235. https://doi.org/10.1002/jsp2.1235

Basatvat S, Bach FC, Barcellona MN, Binch AL, Buckley CT, Bueno B, Cahine NO, Creemers LB, Dudli S, Fearing B, Ferguson SJ, Gansau J, Gantenbein B, Gawri R, Glaeser JD, Grad S, Guerrero J, Haglund L, Hernandez PA, Hoyland JA, Huang C, Iatridis JC, Illien-Junger S, Jing L, Kraus P, Laagland LT, Lang G, Leung V, Li Z, Lufkin T, van Maanen JC, McDonnell EE, Panebiancho CJ, Presciutti SM, Rao S, Richardson SM, Romerein S, Schmitz TC, Schol J, Setton L, Sheyn D, Snuggs JW, Sun Y, Tan X, Tryfonidou MA, Vo N, Wang D, Williams B, Williams R, Yoon ST, Le Maitre CL. Harmonization and standardization of nucleus pulposus cell extraction and culture methods. JOR Spine. 2023;epub Jan 10. https://www.doi.org/10.1002/jsp2.1238

Alini M, Diwan AD, Erwin WM, Little CB, Melrose J. An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics. JOR Spine. 2023;epub Jan 30. https://doi.org/10.1002/jsp2.1230

Leite Pereira C, Grad S, Gonçalves RM. Biomarkers for intervertebral disc and associated back pain: From diagnosis to disease prognosis and personalized treatment. JOR Spine. 2023;epub Oct 2:e1280. https://doi.org/10.1002/jsp2.1280
Presentation

Russo F, Ambrosio L, Peroglio M, Wangler S, Guo W, Grad S, Alini M, Vadalà G, Papalia R, Denaro V. Human mesenchymal stem cells encapsulated in hyaluronic acid and platelet-rich plasma modulate matrix synthesis ex vivo. 2020 EORS virtual (poster)

Cui S, Zhou Z, Alini M, Grad S, Li Z. High impact loading organ culture model to investigate the post-traumatic disc degenerative condition. 2020 GR forscht virtual (oral)

Wangler S, Kamali A, Wapp C, Wuertz-Kozak K, Häckel S, Fortes C, Benneker LM, Haglund L, Richards RG, Alini M, Peroglio M, Grad S.Mesenchymal stem cell secretome: A potential anabolic and immunomodulatory therapy for modulation of early intervertebral disc degeneration. 2021 ORS virtual (oral)

Nüesch A, Zhen Z, Wangler S, Li Z, Grad S. The influence of mesenchymal stromal cells secretome on nucleus pulposus cells exposed to a proinflammatory environment. 2021 SSB+RM YSS (poster)

Wangler S, Kamali A, Wapp C, Wuertz-Kozak K, Häckel S, Fortes C, Benneker LM, Haglund L, Richards RG, Alini M, Peroglio M, Grad S. Mesenchymal stem cell secretome: a potential anabolic and immunomodulatory therapy for early intervertebral disc degeneration. Global Spine J. 2021;11(2 Suppl):102S-3S (Global Spine Congress / oral). https://doi.org/10.1177/21925682211047968

Wangler S, Nüesch A, Chen Z, Häckel S, Albers CE, Bigdon S, Li Z, Alini M, Grad S. MSC secretome as potential immunomodulatory and regenerative treatment strategy for IVD degeneration. ORS 2022 (poster). https://www.ors.org/Transactions/68/961.pdf

Chen S, Croft AS, Bigdon S, Li Z, Oberli AE, Crump KB, Gantenbein B. Conditioned medium from intervertebral disc inhibits autologous mesenchymal stromal cells and osteoblasts. 2023 SSBE (poster)