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Stemness maintenance of stem cells derived from human exfoliated deciduous teeth (SHED) in 3D spheroid formation through the TGF-β/Smad signaling pathway
1Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T., Institute of E.N.T., 518172 Shenzhen, Guangdong, China
2Shenzhen Longgang Institute of Stomatology, 518172 Shenzhen, Guangdong, China
3Longgang District People’s Hospital of Shenzhen, 518116 Shenzhen, Guangdong, China
4Xuzhou Maternity and Child Health Care Hospital, 221009 Xuzhou, Jiangsu, China
DOI: 10.22514/jocpd.2023.081 Vol.47,Issue 6,November 2023 pp.74-85
Submitted: 26 December 2022 Accepted: 12 May 2023
Published: 03 November 2023
*Corresponding Author(s): Jian Xu E-mail: xj-sz@hotmail.com
† These authors contributed equally.
Mesenchymal stem cells (MSCs) have shown great potential as important therapeutic tools for dental pulp tissue engineering, with the maintenance and enhancement of their stemness being crucial for successful therapeutic application in vivo and three-dimensional (3D) spheroid formation considered a reliable technique for enhancing their pluripotency. Human exfoliated deciduous tooth stem cells (SHED) were cultured in a low attachment plate to form aggregates for five days. Then, the resulting spheroids were analyzed for pluripotent marker expression, paracrine secretory function, proliferation, signaling pathways involved, and distribution of key proteins within the spheroids. The results indicated that 3D spheroid formation significantly increased the activation of the transforming growth factor beta (TGF-β)/Smad signaling pathway and upregulated the secretion and mRNA expression levels of TGF-β, which in turn enhanced the expression of pluripotency markers in SHED spheroids. The activation of the TGF-β/Smad signaling pathway through 3D spheroid formation was found to preserve the stemness properties of SHED. Thus, understanding the mechanisms behind pluripotency maintenance of SHED culture through 3D spheroid formation could have implications for the therapeutic application of MSCs in regenerative medicine and tissue engineering.
3D spheroid culture; Stemness maintenance; Stem cells derived from human exfoliated deciduous teeth (SHED); TGF-β/Smad signaling
Hongwen Li,Jing Jiang,Haiying Kong,Wenbo Wu,Xiaomin Shao,Shuqi Qiu,Xianhai Zeng,Qinghong Zhong,Xinhui Yao,Xiantao Zeng,Lingshan Gou,Jian Xu. Stemness maintenance of stem cells derived from human exfoliated deciduous teeth (SHED) in 3D spheroid formation through the TGF-β/Smad signaling pathway. Journal of Clinical Pediatric Dentistry. 2023. 47(6);74-85.
[1] Guo H, Zhao W, Liu A, Wu M, Shuai Y, Li B, et al. SHED promote angiogenesis in stem cell-mediated dental pulp regeneration. Biochemical and Biophysical Research Communications. 2020; 529: 1158–1164.
[2] Liang C, Liao L, Tian W. Stem cell‐based dental pulp regeneration: insights from signaling pathways. Stem Cell Reviews and Reports. 2021; 17: 1251–1263.
[3] Wu M, Liu X, Li Z, Huang X, Guo H, Guo X, et al. SHED aggregate exosomes shuttled miR-26a promote angiogenesis in pulp regeneration via TGF-β/SMAD2/3 signalling. Cell Proliferation. 2021; 54: e13074.
[4] Xu X, Liang C, Gao X, Huang H, Xing X, Tang Q, et al. Adipose tissue–derived microvascular fragments as vascularization units for dental pulp regeneration. Journal of Endodontics. 2021; 47: 1092–1100.
[5] Zhu X, Liu J, Yu Z, Chen CA, Aksel H, Azim AA, et al. A miniature swine model for stem cell-based de novo regeneration of dental pulp and dentin-like tissue. Tissue Engineering Part C: Methods. 2018; 24: 108–120.
[6] Iohara K, Utsunomiya S, Kohara S, Nakashima M. Allogeneic transplantation of mobilized dental pulp stem cells with the mismatched dog leukocyte antigen type is safe and efficacious for total pulp regeneration. Stem Cell Research & Therapy. 2018; 9: 116.
[7] Hilkens P, Bronckaers A, Ratajczak J, Gervois P, Wolfs E, Lambrichts I. The angiogenic potential of DPSCs and SCAPs in an in vivo model of dental pulp regeneration. Stem Cells International. 2017; 2017: 2582080.
[8] Oubenyahya H. Stem cells from dental pulp of human exfoliated teeth: current understanding and future challenges in dental tissue engineering. Stem Cells International. 2021; 24: 9–20.
[9] Mattei V, Delle Monache S. Delle monache dental pulp stem cells (DPSCs) and tissue regeneration: mechanisms mediated by direct, paracrine, or autocrine effects. Biomedicines. 2023; 11: 386.
[10] Anoop M, Datta I. Stem cells derived from human exfoliated deciduous teeth (SHED) in neuronal disorders: a review. Current Stem Cell Research & Therapy. 2021; 16: 535–550.
[11] Fujii Y, Hatori A, Chikazu D, Ogasawara T. Application of dental pulp stem cells for bone and neural tissue regeneration in oral and maxillofacial region. Stem Cells International. 2023; 2023: 2026572.
[12] Bartosh TJ, Ylöstalo JH, Mohammadipoor A, Bazhanov N, Coble K, Claypool K, et al. Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 13724–13729.
[13] Sakai VT, Zhang Z, Dong Z, Neiva KG, Machado MAAM, Shi S, et al. SHED Differentiate into functional odontoblasts and endothelium. Journal of Dental Research. 2010; 89: 791–796.
[14] Mitrano TI, Grob MS, Carrión F, Nova-Lamperti E, Luz PA, Fierro FS, et al. Culture and characterization of mesenchymal stem cells from human gingival tissue. Journal of Periodontology. 2010; 81: 917–925.
[15] Costa MHG, Serra J, McDevitt TC, Cabral JMS, da Silva CL, Ferreira FC. Dimethyloxalylglycine, a small molecule, synergistically increases the homing and angiogenic properties of human mesenchymal stromal cells when cultured as 3D spheroids. Biotechnology Journal. 2021; 16: e2000389.
[16] Shi S, Bartold PM, Miura M, Seo BM, Robey PG, Gronthos S. The efficacy of mesenchymal stem cells to regenerate and repair dental structures. Orthodontics and Craniofacial Research. 2005; 8: 191–199.
[17] Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, et al. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. Journal of Endodontics. 2008; 34: 962–969.
[18] Rosa V, Zhang Z, Grande RH, Nör JE. Dental pulp tissue engineering in full-length human root canals. Journal of Dental Research. 2013; 92: 970–975.
[19] Sugiaman VK, Djuanda R, Pranata N, Naliani S, Demolsky WL, Jeffrey. Tissue Engineering with stem cell from human exfoliated deciduous teeth (SHED) and collagen matrix, regulated by growth factor in regenerating the dental pulp. Polymers. 2022; 14: 3712.
[20] Shi X, Mao J, Liu Y. Pulp stem cells derived from human permanent and deciduous teeth: Biological characteristics and therapeutic applications. Stem Cells Translational Medicine. 2020; 9: 445–464.
[21] Wang SK, Komatsu Y, Mishina Y. Potential contribution of neural crest cells to dental enamel formation. Biochemical and Biophysical Research Communications. 2011; 415: 114–119.
[22] Leathers TA, Rogers CD. Time to go: neural crest cell epithelial-to-mesenchymal transition. Development. 2022; 149: dev200712.
[23] Fan H, Li Y, Yuan F, Lu L, Liu J, Feng W, et al. Up-regulation of microRNA-34a mediates ethanol-induced impairment of neural crest cell migration in vitro and in zebrafish embryos through modulating epithelial-mesenchymal transition by targeting Snail1. Toxicology Letters. 2022; 358: 17–26.
[24] Riekstina U, Cakstina I, Parfejevs V, Hoogduijn M, Jankovskis G, Muiznieks I, et al. Embryonic stem cell marker expression pattern in human mesenchymal stem cells derived from bone marrow, adipose tissue, heart and dermis. Stem Cell Reviews and Reports. 2009; 5: 378–386.
[25] Luk ST, Ng KY, Zhou L, Tong M, Wong TL, Yu H, et al. Deficiency in embryonic stem cell marker reduced expression 1 activates mitogen‐activated protein kinase kinase 6-dependent p38 mitogen‐activated protein kinase signaling to drive hepatocarcinogenesis. Hepatology. 2020; 72: 183–197.
[26] Hung TH, Huang Y, Yeh CT, Yeh CN, Yu J, Lin CC, et al. High expression of embryonic stem cell marker SSEA3 confers poor prognosis and promotes epithelial mesenchymal transition in hepatocellular carcinoma. To be published in Biomedical Journal. 2023. [Preprint].
[27] Kim M, Kim YH, Tae G. Human mesenchymal stem cell culture on heparin-based hydrogels and the modulation of interactions by gel elasticity and heparin amount. Acta Biomaterialia. 2013; 9: 7833–7844.
[28] Diomede F, Rajan TS, Gatta V, D’Aurora M, Merciaro I, Marchisio M, et al. Stemness maintenance properties in human oral stem cells after long-term passage. Stem Cells International. 2017; 2017: 5651287.
[29] Zhang S, Liu P, Chen L, Wang Y, Wang Z, Zhang B. The effects of spheroid formation of adipose-derived stem cells in a microgravity bioreactor on stemness properties and therapeutic potential. Biomaterials. 2015; 41: 15–25.
[30] Bloom AB, Zaman MH. Influence of the microenvironment on cell fate determination and migration. Physiological Genomics. 2014; 46: 309–314.
[31] Chen S, Ikemoto T, Tokunaga T, Okikawa S, Miyazaki K, Yamada S, et al. Newly generated 3D Schwann-like cell spheroids from human adipose-derived stem cells using a modified protocol. Cell Transplantation. 2022; 31: 9636897221093312.
[32] Baraniak PR, Cooke MT, Saeed R, Kinney MA, Fridley KM, McDevitt TC. Stiffening of human mesenchymal stem cell spheroid microenvironments induced by incorporation of gelatin microparticles. Journal of the Mechanical Behavior of Biomedical Materials. 2012; 11: 63–71.
[33] Yamada Y, Okano T, Orita K, Makino T, Shima F, Nakamura H. 3D-cultured small size adipose-derived stem cell spheroids promote bone regeneration in the critical-sized bone defect rat model. Biochemical and Biophysical Research Communications. 2022; 603: 57–62.
[34] McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell Shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Developmental Cell. 2004; 6: 483–495.
[35] Cesarz Z, Tamama K. Spheroid culture of mesenchymal stem cells. Stem Cells International. 2016; 2016: 9176357.
[36] Vidyasekar P, Shyamsunder P, Sahoo SK, Verma RS. Scaffold-free and scaffold-assisted 3D culture enhances differentiation of bone marrow stromal cells. In Vitro Cellular & Developmental Biology—Animal. 2016; 52: 204–217.
[37] Di Stefano AB, Grisafi F, Perez-Alea M, Castiglia M, Di Simone M, Meraviglia S, et al. Cell quality evaluation with gene expression analysis of spheroids (3D) and adherent (2D) adipose stem cells. Gene. 2021; 768: 145269.
[38] Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell. 2007; 130: 601–610.
[39] Kim HJ, Sung IY, Cho YC, Kang MS, Rho GJ, Byun JH, et al. Three-dimensional spheroid formation of cryopreserved human dental follicle-derived stem cells enhances pluripotency and osteogenic induction properties. Tissue Engineering and Regenerative Medicine. 2019; 16: 513–523.
[40] Potapova IA, Gaudette GR, Brink PR, Robinson RB, Rosen MR, Cohen IS, et al. Mesenchymal stem cells support migration, extracellular matrix invasion, proliferation, and survival of endothelial cells in vitro. Stem Cells. 2007; 25: 1761–1768.
[41] Frith JE, Thomson B, Genever PG. Dynamic three-dimensional culture methods enhance mesenchymal stem cell properties and increase therapeutic potential. Tissue Engineering Part C: Methods. 2010; 16: 735–749.
[42] Kim SJ, Kim EM, Yamamoto M, Park H, Shin H. Engineering multi‐cellular spheroids for tissue engineering and regenerative medicine. To be published in Advanced Healthcare Materials. 2020. [Preprint].
[43] Chen LC, Wang HW, Huang CC. Modulation of inherent niches in 3D multicellular MSC spheroids reconfigures metabolism and enhances therapeutic potential. Cells. 2021; 10: 2747.
[44] Choi J, Choi W, Joo Y, Chung H, Kim D, Oh SJ, et al. FGF2-primed 3D spheroids producing IL-8 promote therapeutic angiogenesis in murine hindlimb ischemia. NPJ Regenerative Medicine. 2021; 6: 48.
[45] Hosseini V, Maroufi NF, Saghati S, Asadi N, Darabi M, Ahmad SNS, et al. Current progress in hepatic tissue regeneration by tissue engineering. Journal of Translational Medicine. 2019; 17: 383.
[46] Macková H, Hlídková H, Kaberova Z, Proks V, Kučka J, Patsula V, et al. Thiolated poly (2-hydroxyethyl methacrylate) hydrogels as a degradable biocompatible scaffold for tissue engineering. Materials Science and Engineering: C. 2021; 131: 112500.
[47] Chang PC, Lin ZJ, Luo HT, Tu CC, Tai WC, Chang CH, et al. Degradable RGD-functionalized 3D-printed scaffold promotes osteogenesis. Journal of Dental Research. 2021; 100: 1109–1117.
[48] Williams DF. On the mechanisms of biocompatibility. Biomaterials. 2008; 29: 2941–2953.
[49] Cheng NC, Wang S, Young TH. The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities. Biomaterials. 2012; 33: 1748–1758.
[50] Kasprzak C, Brown JR, Feller K, Scott PJ, Meenakshisundaram V, Williams C, et al. Vat photopolymerization of reinforced Styrene-Butadiene elastomers: a degradable scaffold approach. ACS Applied Materials & Interfaces. 2022; 14: 18965–18973.
[51] Li SN, Wu JF. TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment. Stem Cell Research & Therapy. 2020; 11: 41.
[52] Xu RH, Sampsell-Barron TL, Gu F, Root S, Peck RM, Pan G, et al. NANOG is a direct target of TGF-β/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell. 2008; 3: 196–206.
[53] Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development. 2009; 136: 1339–1349.
[54] Guo L, Zhou Y, Wang S, Wu Y. Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids. Journal of Cellular and Molecular Medicine. 2014; 18: 2009–2019.
[55] Han X, Tang S, Wang L, Xu X, Yan R, Yan S, et al. Multicellular spheroids formation on hydrogel enhances osteogenic/odontogenic differentiation of dental pulp stem cells under magnetic nanoparticles induction. International Journal of Nanomedicine. 2021; 16: 5101–5115.
[56] Stuart MP, Matsui RAM, Santos MFS, Côrtes I, Azevedo MS, Silva KR, et al. Successful low-cost scaffold-free cartilage tissue engineering using human cartilage progenitor cell spheroids formed by micromolded nonadhesive hydrogel. Stem Cells International. 2017; 2017: 7053465.
[57] Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, et al. SHED: stem cells from human exfoliated deciduous teeth. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 5807–5812.
[58] Elsafadi M, Shinwari T, Al-Malki S, Manikandan M, Mahmood A, Aldahmash A, et al. Convergence of TGF-β and BMP signaling in regulating human bone marrow stromal cell differentiation. Scientific Reports. 2019; 9: 4977.
[59] Kim D, Lee AE, Xu Q, Zhang Q, Le AD. Gingiva-derived mesenchymal stem cells: potential application in tissue engineering and regenerative medicine—a comprehensive review. Frontiers in Immunology. 2021; 12: 667221.
[60] Zhou H, He Y, Xiong W, Jing S, Duan X, Huang Z, et al. MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases. Bioactive Materials. 2022; 23: 409–437.
[61] Prasajak P, Rattananinsruang P, Chotinantakul K, Dechsukhum C, Leeanansaksiri W. Embryonic stem cells conditioned medium enhances Wharton’s jelly-derived mesenchymal stem cells expansion under hypoxic condition. Cytotechnology. 2015; 67: 493–505.
[62] Park E, Patel AN. Changes in the expression pattern of mesenchymal and pluripotent markers in human adipose-derived stem cells. Cell Biology International. 2010; 34: 979–984.
[63] Chen K, Li X, Li N, Dong H, Zhang Y, Yoshizawa M, et al. Spontaneously formed spheroids from mouse compact bone-derived cells retain highly potent stem cells with enhanced differentiation capability. Stem Cells International. 2019; 2019: 8469012.
[64] Yamamoto M, Kawashima N, Takashino N, Koizumi Y, Takimoto K, Suzuki N, et al. Three-dimensional spheroid culture promotes odonto/osteoblastic differentiation of dental pulp cells. Archives of Oral Biology. 2014; 59: 310–317.
[65] Drela K, Sarnowska A, Siedlecka P, Szablowska-Gadomska I, Wielgos M, Jurga M, et al. Low oxygen atmosphere facilitates proliferation and maintains undifferentiated state of umbilical cord mesenchymal stem cells in an hypoxia inducible factor-dependent manner. Cytotherapy. 2014; 16: 881–892.
[66] Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Developmental Cell. 2005; 9: 617–628.
[67] Dong L, Wang Y, Zheng T, Pu Y, Ma Y, Qi X, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Research & Therapy. 2021; 12: 4.
[68] Gorgun C, Ceresa D, Lesage R, Villa F, Reverberi D, Balbi C, et al. Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs). Biomaterials. 2021; 269: 120633.
[69] Guo L, Zhao RCH, Wu Y. The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Experimental Hematology. 2011; 39: 608–616.
[70] Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature. 2012; 482: 524–528.
[71] Zhang D, Kilian KA. The effect of mesenchymal stem cell shape on the maintenance of multipotency. Biomaterials. 2013; 34: 3962–3969.
[72] Jozkowiak M, Hutchings G, Jankowski M, Kulcenty K, Mozdziak P, Kempisty B, et al. The stemness of human ovarian granulosa cells and the role of resveratrol in the differentiation of MSCs—a review based on cellular and molecular knowledge. Cells. 2020; 9: 1418.
[73] Moritani Y, Usui M, Sano K, Nakazawa K, Hanatani T, Nakatomi M, et al. Spheroid culture enhances osteogenic potential of periodontal ligament mesenchymal stem cells. Journal of Periodontal Research. 2018; 53: 870–882.
[74] Gonzalez-Fernandez T, Tenorio AJ, Saiz AM Jr, Leach JK. Engineered cell-secreted extracellular matrix modulates cell spheroid mechanosensing and amplifies their response to inductive cues for the formation of mineralized tissues. Advanced Healthcare Materials. 2022; 11: e2102337.
[75] Raik S, Sharma P, Kumar S, Rattan V, Das A, Kumar N, et al. Three-dimensional spheroid culture of dental pulp-derived stromal cells enhance their biological and regenerative properties for potential therapeutic applications. The International Journal of Biochemistry & Cell Biology. 2023; 160: 106422.
[76] Liu F, Qiu H, Xue M, Zhang S, Zhang X, Xu J, et al. MSC-secreted TGF-β regulates lipopolysaccharide-stimulated macrophage M2-like polarization via the Akt/FoxO1 pathway. Stem Cell Research & Therapy. 2019; 10: 345.
[77] Ashraf R, Sofi HS, Sheikh FA. Experimental protocol of MSC differentiation into neural lineage for nerve tissue regeneration using polymeric scaffolds. Methods in Molecular Biology. 2020; 2125: 109–117.
[78] Xu Y, Shi T, Xu A, Zhang L. 3D spheroid culture enhances survival and therapeutic capacities of MSCs injected into ischemic kidney. Journal of Cellular and Molecular Medicine. 2016; 20: 1203–1213.
[79] Grafe I, Alexander S, Peterson JR, Snider TN, Levi B, Lee B, et al. TGF-β family signaling in mesenchymal differentiation. Cold Spring Harbor Perspectives in Biology. 2018; 10: a022202.
[80] de la Grange P, Jolly A, Courageux C, Ben Brahim C, Leroy P. Genes coding for transcription factors involved in stem cell maintenance are repressed by TGF-β and downstream of Slug/Snail2 in COPD bronchial epithelial progenitors. Molecular Biology Reports. 2021; 48: 6729–6738.
[81] Zimmermann JA, Mcdevitt TC. Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion. Cytotherapy. 2014; 16: 331–345.
[82] Mochizuki Y, Kogawa R, Takegami R, Nakamura K, Wakabayashi A. Co-microencapsulation of islets and MSC CellSaics, mosaic-like aggregates of MSCs and recombinant peptide pieces, and therapeutic effects of their subcutaneous transplantation on diabetes. Biomedicines. 2020; 8: 318.
[83] Itoh F, Watabe T, Miyazono K. Roles of TGF-β family signals in the fate determination of pluripotent stem cells. Seminars in Cell & Developmental Biology. 2014; 32: 98–106.
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