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The human dental apical papilla promotes spinal cord repair through a paracrine mechanism

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Abstract

Traumatic spinal cord injury is an overwhelming condition that strongly and suddenly impacts the patient’s life and her/his entourage. There are currently no predictable treatments to repair the spinal cord, while many strategies are proposed and evaluated by researchers throughout the world. One of the most promising avenues is the transplantation of stem cells, although its therapeutic efficiency is limited by several factors, among which cell survival at the lesion site. In our previous study, we showed that the implantation of a human dental apical papilla, residence of stem cells of the apical papilla (SCAP), supported functional recovery in a rat model of spinal cord hemisection. In this study, we employed protein multiplex, immunohistochemistry, cytokine arrays, RT- qPCR, and RNAseq technology to decipher the mechanism by which the dental papilla promotes repair of the injured spinal cord. We found that the apical papilla reduced inflammation at the lesion site, had a neuroprotective effect on motoneurons, and increased the apoptosis of activated macrophages/ microglia. This therapeutic effect is likely driven by the secretome of the implanted papilla since it is known to secrete an entourage of immunomodulatory or pro-angiogenic factors. Therefore, we hypothesize that the secreted molecules were mainly produced by SCAP, and that by anchoring and protecting them, the human papilla provides a protective niche ensuring that SCAP could exert their therapeutic actions. Therapeutic abilities of the papilla were demonstrated in the scope of spinal cord injury but could very well be beneficial to other types of tissue.

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Data availability

The dataset generated and analyzed during the current study is available in the GEO repository under the number GSE191140 at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE191140.

References

  1. Vismara I, Papa S, Rossi F, Forloni G, Veglianese P (2017) Current options for cell therapy in spinal cord injury. Trends Mol Med 23(9):831–849. https://doi.org/10.1016/j.molmed.2017.07.005

    Article  CAS  PubMed  Google Scholar 

  2. Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57. https://doi.org/10.1016/j.pneurobio.2013.11.002

    Article  PubMed  Google Scholar 

  3. Flack JA, Sharma KD, Xie JY (2022) Delving into the recent advancements of spinal cord injury treatment: a review of recent progress. Neural Regen Res 17(2):283–291. https://doi.org/10.4103/1673-5374.317961

    Article  PubMed  Google Scholar 

  4. des Rieux A (2021) Stem cells and their extracellular vesicles as natural and bioinspired carriers for the treatment of neurological disorders. Curr Opin Colloid Interface Sci 54:101460. https://doi.org/10.1016/j.cocis.2021.101460

    Article  CAS  Google Scholar 

  5. Bonaventura G, Incontro S, Iemmolo R, La Cognata V, Barbagallo I, Costanzo E, Barcellona ML, Pellitteri R, Cavallaro S (2020) Dental mesenchymal stem cells and neuro- regeneration: a focus on spinal cord injury. Cell Tissue Res 379(3):421–428. https://doi.org/10.1007/s00441-019-03109-4

    Article  PubMed  Google Scholar 

  6. Bianco J, De Berdt P, Deumens R, des Rieux A (2016) Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it? Cell Mol Life Sci 73(7):1413–37. https://doi.org/10.1007/s00018-015-2126-5

    Article  CAS  PubMed  Google Scholar 

  7. Huang GT, Gronthos S, Shi S (2009) Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res 88(9):792–806. https://doi.org/10.1177/0022034509340867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sonoyama W, Liu Y, Yamaza T, Tuan RS, Wang S, Shi S, Huang GT (2008) Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study. J Endod 34(2):166–171. https://doi.org/10.1016/j.joen.2007.11.021

    Article  PubMed  PubMed Central  Google Scholar 

  9. Huang GT, Sonoyama W, Liu Y, Liu H, Wang S, Shi S (2008) The hidden treasure in apical papilla: the potential role in pulp/dentin regeneration and bioroot engineering. J Endod 34(6):645–651. https://doi.org/10.1016/j.joen.2008.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  10. De Berdt P, Bottemanne P, Bianco J, Alhouayek M, Diogenes A, Lloyd A, Llyod A, Gerardo-Nava J, Brook GA, Miron V, Muccioli GG, Rieux AD (2018) Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion. Cell Mol Life Sci 75(15):2843–2856. https://doi.org/10.1007/s00018-018-2764-5

    Article  CAS  PubMed  Google Scholar 

  11. De Berdt P, Vanacker J, Ucakar B, Elens L, Diogenes A, Leprince JG, Deumens R, des Rieux A (2015) Dental apical papilla as therapy for spinal cord injury. J Dent Res 94(11):1575–81. https://doi.org/10.1177/0022034515604612

    Article  PubMed  Google Scholar 

  12. Huang GT (2008) A paradigm shift in endodontic management of immature teeth: conservation of stem cells for regeneration. J Dent 36(6):379–386. https://doi.org/10.1016/j.jdent.2008.03.002

    Article  PubMed  Google Scholar 

  13. Ruparel NB, de Almeida JF, Henry MA, Diogenes A (2013) Characterization of a stem cell of apical papilla cell line: effect of passage on cellular phenotype. J Endod 39(3):357–363. https://doi.org/10.1016/j.joen.2012.10.027

    Article  PubMed  Google Scholar 

  14. Vanacker J, Viswanath A, De Berdt P, Everard A, Cani PD, Bouzin C, Feron O, Diogenes A, Leprince JG, des Rieux A (2014) Hypoxia modulates the differentiation potential of stem cells of the apical papilla. J Endod 40(9):1410–1418. https://doi.org/10.1016/j.joen.2014.04.008

    Article  PubMed  Google Scholar 

  15. Schira J, Gasis M, Estrada V, Hendricks M, Schmitz C, Trapp T, Kruse F, Kogler G, Wernet P, Hartung HP, Muller HW (2012) Significant clinical, neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Brain 135(Pt 2):431–446. https://doi.org/10.1093/brain/awr222

    Article  PubMed  Google Scholar 

  16. Kandalam S, De Berdt P, Ucakar B, Vanvarenberg K, Bouzin C, Gratpain V, Diogenes A, Montero-Menei CN, des Rieux A (2020) Human dental stem cells of the apical papilla associated to BDNF-loaded pharmacologically active microcarriers (PAMs) enhance locomotor function after spinal cord injury. Int J Pharm 587:119685. https://doi.org/10.1016/j.ijpharm.2020.119685

    Article  CAS  PubMed  Google Scholar 

  17. De Berdt P, Bottemanne P, Bianco J, Alhouayek M, Diogenes A, Llyod A, Gerardo-Nava J, Brook GA, Miron V, Muccioli GG, Rieux AD (2018) Stem cells from human apical papilla decrease neuro-inflammation and stimulate oligodendrocyte progenitor differentiation via activin-A secretion. Cell Mol Life Sci 75(15):2843–2856. https://doi.org/10.1007/s00018-018-2764-5

    Article  CAS  PubMed  Google Scholar 

  18. Hached F, Vinatier C, Pinta PG, Hulin P, Le Visage C, Weiss P, Guicheux J, Billon- Chabaud A, Grimandi G (2017) Polysaccharide hydrogels support the long-term viability of encapsulated human mesenchymal stem cells and their ability to secrete immunomodulatory factors. Stem Cells Int 2017:9303598. https://doi.org/10.1155/2017/9303598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buisseret B, Guillemot-Legris O, Ben Kouidar Y, Paquot A, Muccioli GG, Alhouayek M (2021) Effects of R-flurbiprofen and the oxygenated metabolites of endocannabinoids in inflammatory pain mice models. FASEB J 35(4):e21411. https://doi.org/10.1096/fj.202002468R

    Article  CAS  PubMed  Google Scholar 

  20. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics 30(15):2114–2120. https://doi.org/10.1093/bioinformatics/btu170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12(4):357–360. https://doi.org/10.1038/nmeth.3317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liao Y, Smyth GK, Shi W (2014) Featurecounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30(7):923–930. https://doi.org/10.1093/bioinformatics/btt656

    Article  CAS  PubMed  Google Scholar 

  23. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550. https://doi.org/10.1186/s13059-014-0550-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yu G, Wang LG, Han Y, He QY (2012) Clusterprofiler: an R package for comparing biological themes among gene clusters. OMICS 16(5):284–287. https://doi.org/10.1089/omi.2011.0118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ghosh M, Pearse DD (2014) The role of the serotonergic system in locomotor recovery after spinal cord injury. Front Neural Circuits 8:151. https://doi.org/10.3389/fncir.2014.00151

    Article  PubMed  Google Scholar 

  26. Sarikaya A, Aydin G, Ozyuncu O, Sahin E, Uckan-Cetinkaya D, Aerts-Kaya F (2021) Comparison of immune modulatory properties of human multipotent mesenchymal stromal cells derived from bone marrow and placenta. Biotech Histochem. https://doi.org/10.1080/10520295.2021.1885739

    Article  PubMed  Google Scholar 

  27. An N, Yang J, Wang H, Sun S, Wu H, Li L, Li M (2021) Mechanism of mesenchymal stem cells in spinal cord injury repair through macrophage polarization. Cell Biosci 11(1):41. https://doi.org/10.1186/s13578-021-00554-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu XB, He LN, Jiang BC, Shi H, Bai XQ, Zhang WW, Gao YJ (2018) Spinal CXCL9 and CXCL11 are not involved in neuropathic pain despite an upregulation in the spinal cord following spinal nerve injury. Mol Pain 14:1744806918777401. https://doi.org/10.1177/1744806918777401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kwiatkowski K, Popiolek-Barczyk K, Piotrowska A, Rojewska E, Ciapała K, Makuch W, Mika J (2019) Chemokines CCL2 and CCL7, but not CCL12, play a significant role in the development of pain-related behavior and opioid-induced analgesia. Cytokine 119:202–213. https://doi.org/10.1016/j.cyto.2019.03.007

    Article  CAS  PubMed  Google Scholar 

  30. Yu WR, Fehlings MG (2011) Fas/FasL-mediated apoptosis and inflammation are key features of acute human spinal cord injury: implications for translational, clinical application. Acta Neuropathol 122(6):747–761. https://doi.org/10.1007/s00401-011-0882-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang G, Zha J, Liu J, Di J (2019) Minocycline impedes mitochondrial-dependent cell death and stabilizes expression of hypoxia inducible factor-1alpha in spinal cord injury. Arch Med Sci 15(2):475–483. https://doi.org/10.5114/aoms.2018.73520

    Article  CAS  PubMed  Google Scholar 

  32. Nakazaki M, Morita T, Lankford KL, Askenase PW, Kocsis JD (2021) Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF-beta upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury. J Extracell Vesicles 10(11):e12137. https://doi.org/10.1002/jev2.12137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sykova E, Cizkova D, Kubinova S (2021) Mesenchymal stem cells in treatment of spinal cord injury and amyotrophic lateral sclerosis. Front Cell Dev Biol 9:695900. https://doi.org/10.3389/fcell.2021.695900

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE (2019) Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci 22(7):1046–1052. https://doi.org/10.1038/s41593-019-0418-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Perrin FE, Noristani HN (2019) Serotonergic mechanisms in spinal cord injury. Exp Neurol 318:174–191. https://doi.org/10.1016/j.expneurol.2019.05.007

    Article  CAS  PubMed  Google Scholar 

  36. Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX (2020) Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci 10:112. https://doi.org/10.1186/s13578-020-00475-3

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sorrell JM, Baber MA, Caplan AI (2009) Influence of adult mesenchymal stem cells on in vitro vascular formation. Tissue Eng Part A 15(7):1751–1761. https://doi.org/10.1089/ten.tea.2008.0254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hofer HR, Tuan RS (2016) Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 7(1):131. https://doi.org/10.1186/s13287-016-0394-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Song P, Han T, Xiang X, Wang Y, Fang H, Niu Y, Shen C (2020) The role of hepatocyte growth factor in mesenchymal stem cell-induced recovery in spinal cord injured rats. Stem Cell Res Ther 11(1):178. https://doi.org/10.1186/s13287-020-01691-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yu S, Zhao Y, Ma Y, Ge L (2016) Profiling the secretome of human stem cells from dental apical papilla. Stem Cells Dev 25(6):499–508. https://doi.org/10.1089/scd.2015.0298

    Article  CAS  PubMed  Google Scholar 

  41. Diogenes A, Henry MA, Teixeira FB, Hargreaves KM (2013) An update on clinical regenerative endodontics. Endodontic Topics 28(1):2–23. https://doi.org/10.1111/etp.12040

    Article  Google Scholar 

  42. Alekseenko LL, Shilina MA, Lyublinskaya OG, Kornienko JS, Anatskaya OV, Vinogradov AE, Grinchuk TM, Fridlyanskaya II, Nikolsky NN (2018) Quiescent human mesenchymal stem cells are more resistant to heat stress than cycling cells. Stem Cells Int 2018:3753547. https://doi.org/10.1155/2018/3753547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Song N, Scholtemeijer M, Shah K (2020) Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci 41(9):653–664. https://doi.org/10.1016/j.tips.2020.06.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Desole C, Gallo S, Vitacolonna A, Montarolo F, Bertolotto A, Vivien D, Comoglio P, Crepaldi T (2021) HGF and MET: from brain development to neurological disorders. Front Cell Dev Biol 9:683609. https://doi.org/10.3389/fcell.2021.683609

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li H, Deng Y, Liang J, Huang F, Qiu W, Zhang M, Long Y, Hu X, Lu Z, Liu W, Zheng SG (2019) Mesenchymal stromal cells attenuate multiple sclerosis via IDO-dependent increasing the suppressive proportion of CD5+ IL-10+ B cells. Am J Transl Res 11(9):5673–5688

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang S, Fang J, Liu Z, Hou P, Cao L, Zhang Y, Liu R, Li Y, Shang Q, Chen Y, Feng C, Wang G, Melino G, Wang Y, Shao C, Shi Y (2021) Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis. Stem Cell Res Ther 12(1):50. https://doi.org/10.1186/s13287-020-02118-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xin D, Li T, Chu X, Ke H, Yu Z, Cao L, Bai X, Liu D, Wang Z (2020) Mesenchymal stromal cell-derived extracellular vesicles modulate microglia/macrophage polarization and protect the brain against hypoxia-ischemic injury in neonatal mice by targeting delivery of miR-21a-5p. Acta Biomater 113:597–613. https://doi.org/10.1016/j.actbio.2020.06.037

    Article  CAS  PubMed  Google Scholar 

  48. Khare D, Or R, Resnick I, Barkatz C, Almogi-Hazan O, Avni B (2018) Mesenchymal stromal cell-derived exosomes affect mRNA expression and function of B-Lymphocytes. Front Immunol 9:3053. https://doi.org/10.3389/fimmu.2018.03053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the Stockel Dental Practice for their support and for providing wisdom teeth as well as Prof. Julian Leprince (LDRI/UCLouvain) for fruitful discussions. The authors would also like to thank Prof. Catherine Levisage (Nantes University, RMeS) for constructive criticisms that contributed to improve the manuscript.

Funding

Anne des Rieux is a F.R.S.-FNRS Senior Research Associate and is a recipient of a grant from the International Foundation of Research in Paraplegia [P155]. This work was supported by the F.R.S.-FNRS and a grant from the International Foundation of Research in Paraplegia [P155]. The authors have no relevant financial or non-financial interests to disclose.

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Authors and Affiliations

  1. Louvain Drug Research Institute (LDRI), Advanced Drug Delivery and Biomaterials (ADDB), Université Catholique de Louvain (UCLouvain), 1200, Brussels, Belgium

    P. De Berdt, K. Vanvarenberg, B. Ucakar, V. Gratpain, V. Payen & A. des Rieux

  2. IREC Imaging platform (2IP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200, Brussels, Belgium

    C. Bouzin

  3. Louvain Drug Research Institute (LDRI), Bioanalysis and Pharmacology of Bioactive Lipids (BPBL), Université Catholique de Louvain (UCLouvain), 1200, Brussels, Belgium

    A. Paquot & G. G. Muccioli

  4. de Duve Institute, Computational Biology and Bioinformatics Unit (CBIO), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

    A. Loriot & L. Gatto

  5. Institut de Recherche Expérimentale et Clinique (IREC), Center for Applied Molecular Technologies (CTMA), Université Catholique de Louvain (UCLouvain), Brussels, Belgium

    B. Bearzatto

  6. Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    A. Diogenes

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  1. P. De Berdt
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  2. K. Vanvarenberg
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  10. G. G. Muccioli
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  11. L. Gatto
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  12. A. Diogenes
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Contributions

All the authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by PDB, KV, BU, VG, VP, and BB. CB: designed the algorithms and did the quantification of the immunofluorescence staining. AP and GGM: performed the PG2E quantification. A. Diogenes performed the genetic and proteomic analysis of spinal cord tissues. AL and LG: did the statistical analysis of the RNAseq data. The first draft of the manuscript was written by PDB: and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

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Correspondence to A. des Rieux.

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De Berdt, P., Vanvarenberg, K., Ucakar, B. et al. The human dental apical papilla promotes spinal cord repair through a paracrine mechanism. Cell. Mol. Life Sci. 79, 252 (2022). https://doi.org/10.1007/s00018-022-04210-8

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