Abstract
Programmed cell death-1 (PD-1) belongs to an inhibitory signaling pathway capable of maintaining central and peripheral immune tolerance. Blockage of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases. However, it is unknown whether PD-1 pathway regulates stem cell function. It is generally believed that mesenchymal stem cells (MSCs) produce PD-1 ligand, but fail to express PD-1. In this study, we show that neural crest-derived MSCs from dental pulp (MSC-DP), but not MSCs from bone marrow, expressed PD-1. Knocking down PD-1 expression in MSC-DP results in a significantly reduced capacity for cell proliferation and accelerated multipotential differentiation. Mechanistically, we show that PD-1 regulates a SHP2/ERK/Notch cascade to maintain proliferation and a SHP2/ERK/β-catenin cascade to inhibit osteo-/odontogenic differentiation. This study indicates that PD-1 is a key surface molecule controlling cell proliferation and multipotential differentiation of MSC-DP. Through regulating PD-1/SHP2/ERK signaling, we can significantly improve the quality and quantity of culture-expanded MSC-DP for potential clinical therapies.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Chung IH, Yamaza T, Zhao H, Choung PH, Shi S, Chai Y. Stem cell property of postmigratory cranial neural crest cells and their utility in alveolar bone regeneration and tooth development. Stem Cells. 2009;4:866–77.
Zhao H, Chai Y. Stem cells in teeth and craniofacial bones. J Dent Res. 2015;94:1495–501.
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA. 2000;97:13625–30.
Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, et al. Stem cell properties of human dental pulp stem cells. J Dent Res. 2002;81:531–5.
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA. 2003;100:5807–12.
Sakai VT, Zhang Z, Dong Z, Neiva KG, Machado MA, Shi S, et al. SHED differentiate into functional odontoblasts and endothelium. J Dent Res. 2010;89:791–6.
Zhao Y, Wang L, Jin Y, Shi S. Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J Dent Res. 2012;91:948–54.
Li Z, Jiang CM, An S, Cheng Q, Huang YF, Wang YT, et al. Immunomodulatory properties of dental tissue-derived mesenchymal stem cells. Oral Dis. 2014;20:25–34.
Yamaza T, Kentaro A, Chen C, Liu Y, Shi Y, Gronthos S, et al. Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res Ther. 2010;1:5.
Liu Y, Wang L, Liu SY, Liu DW, Chen C, Xu XT, et al. Transplantation of SHED prevents bone loss in the early phase of ovariectomy-induced osteoporosis. J Dent Res. 2014;93:1124–32.
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–95.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.
Latchman Y, Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.
Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21:24–33.
English K, Barry FP, Field-Corbett CP, Mahon BPIFN-gamma. and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett. 2007;110:91–100.
Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014;153:145–52.
Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011;350:17–37.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945–54.
Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–17.
Feng GS. Shp2-mediated molecular signaling in control of embryonic stem cell /proliferation and differentiation. Cell Res. 2007;17:37–41.
Liu J, Sato C, Cerletti M, Wagers A. Notch signaling in the regulation of stem cell self-renewal/proliferation and differentiation. Curr Top Dev Biol. 2010;92:367–409.
Liu Y, Chen C, Liu SY, Liu DW, Xu XT, Chen X, Shi S. Acetylsalicylic acid treatment improves differentiation and immunomodulation of SHED. J Dent Res. 2015;94:209–18.
Chen L, Pai V, Levinson R, Sharpe AH, Freeman GJ, Braun J, et al. Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis. Ocul Immunol Inflamm. 2009a;17:47–55.
Chen L, Sham CW, Chan AM, Francisco LM, Wu Y, Mareninov S, et al. Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells. Invest Ophthalmol Vis Sci. 2009b;50:4941–8.
Wang W, Chan A, Qin Y, Kwong JM, Caprioli J, Levinson R, et al. Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush. Exp Eye Res. 2015;140:1–9.
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35:1482–90.
Ma L, Makino Y, Yamaza H, Akiyama K, Hoshino Y, Song G, et al. Cryopreserved dental pulp tissues of exfoliated deciduous teeth is a feasible stem cell resource for regenerative medicine. PLoS ONE. 2012;7:e51777.
Jeon M, Song JS, Choi BJ, Choi HJ, Shin DM, Jung HS, et al. In vitro and in vivo characteristics of stem cells from human exfoliated deciduous teeth obtained by enzymatic disaggregation and outgrowth. Arch Oral Biol. 2014;59:1013–23.
Nakamura T, Gulick J, Colbert MC, Robbins J. Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development. Proc Natl Acad Sci USA. 2009;106:11270–5.
Stewart RA, Sanda T, Widlund HR, Zhu S, Swanson KD, Hurley AD, et al. Phosphatase dependent and independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Dev Cell. 2010;18:750–62.
Neel BG, Gu H, Pao L. The shping news: SH2 domain-containing protein tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–93.
Schindeler A, Little DG. Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res. 2006;21:1331–8.
Jaiswal RK, Jaiswal N, Bruder SP, Mbalaviele G, Marshak DR, Pittenger MF. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem. 2000;275:9645–52.
Kretzschmar M, Doody J, Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature. 1997;389:618–22.
Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, et al. Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. J Bone Miner Res. 2002;17:1785–94.
Shi S, Gronthos S, Chen S, Reddi A, Counter CM, Robey PG, et al. Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol. 2002;20:587–91.
Acknowledgements
This work was supported by Beijing Tason Biotech Co. LTD and National Natural Science Foundation of China (81600825 to Y.L.).
Author contributions
Y.L. designed and performed the experiments, analyzed and interpreted the data, and wrote the manuscript. H.J., X.X., C.C., and D.L. performed the experiments and analyzed and interpreted the data. Y.J., L.L., and S.S. designed the experiments, analyzed the data, wrote the manuscript, and supervised the laboratory studies.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Liu, Y., Jing, H., Kou, X. et al. PD-1 is required to maintain stem cell properties in human dental pulp stem cells. Cell Death Differ 25, 1350–1360 (2018). https://doi.org/10.1038/s41418-018-0077-8
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41418-018-0077-8
This article is cited by
-
Human cytomegalovirus infection impairs neural differentiation via repressing sterol regulatory element binding protein 2-mediated cholesterol biosynthesis
Cellular and Molecular Life Sciences (2024)
-
TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment
Journal of Translational Medicine (2022)
-
Blockade of PD-L1/PD-1 signaling promotes osteo-/odontogenic differentiation through Ras activation
International Journal of Oral Science (2022)
-
CD146 controls the quality of clinical grade mesenchymal stem cells from human dental pulp
Stem Cell Research & Therapy (2021)
-
Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells
Stem Cell Research & Therapy (2021)
