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Developmental function of Piezo1 in mouse submandibular gland morphogenesis

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Abstract

Mechanically activated factors are important in organogenesis, especially in the formation of secretory organs, such as salivary glands. Piezo-type mechanosensitive ion channel component 1 (Piezo1), although previously studied as a physical modulator of the mechanotransduction, was firstly evaluated on its developmental function in this study. The detailed localization and expression pattern of Piezo1 during mouse submandibular gland (SMG) development were analyzed using immunohistochemistry and RT-qPCR, respectively. The specific expression pattern of Piezo1 was examined in acinar-forming epithelial cells at embryonic day 14 (E14) and E16, which are important developmental stages for acinar cell differentiation. To understand the precise function of Piezo1 in SMG development, siRNA against Piezo1 (siPiezo1) was employed as a loss-of-function approach, during in vitro organ cultivation of SMG at E14 for the designated period. Alterations in the histomorphology and expression patterns of related signaling molecules, including Bmp2, Fgf4, Fgf10, Gli1, Gli3, Ptch1, Shh, and Tgfβ-3, were examined in acinar-forming cells after 1 and 2 days of cultivation. Particularly, altered localization patterns of differentiation-related signaling molecules including Aquaporin5, E-cadherin, Vimentin, and cytokeratins would suggest that Piezo1 modulates the early differentiation of acinar cells in SMGs by modulating the Shh signaling pathway.

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References

  • Adhikari N, Neupane S, Gwon G-J, Kim J-Y, An C-H, Lee S, Sohn W-J, Lee Y, Kim J-Y (2017) Grhl3 modulates epithelial structure formation of the circumvallate papilla during mouse development. J Mol Histol 147(1):5–16

    CAS  Google Scholar 

  • Adhikari N, Neupane S, Roh J, Jun JH, Jung J-K, Sohn W-J, Kim J-Y, Kim J-Y (2018) Immunolocalization patterns of cytokeratins during salivary acinar cell development in mice. J Mol Histol 49(1):1–15

    Article  CAS  PubMed  Google Scholar 

  • Alam H, Sehgal L, Kundu ST, Dalal SN, Vaidya MM (2011) Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells. Mol Biol Cell 22(21):4068–4078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aryal YP, Neupane S, Kim T-Y, Lee E-S, Pokhrel NK, Yeon C-Y, Kim J-Y, An C-H, An S-Y, Park E-K (2020) Developmental roles of FUSE binding protein 1 (Fubp1) in tooth morphogenesis. Int J Mol Sci 21:8079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atcha H, Jairaman A, Holt JR, Meli VS, Nagalla RR, Veerasubramanian PK, Brumm KT, Lim HE, Othy S, Cahalan MD (2021) Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Nat Commun 12(1):3256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aure MH, Larsen HS, Ruus A-K, Galtung HK (2011) Aquaporin 5 distribution pattern during development of the mouse sublingual salivary gland. J Mol Histol 42(5):401–408

    Article  CAS  PubMed  Google Scholar 

  • Caulier A, Jankovsky N, Demont Y, Ouled-Haddou H, Demagny J, Guitton C, Merlusca L, Lebon D, Vong P, Aubry A (2020) PIEZO1 activation delays erythroid differentiation of normal and hereditary xerocytosis-derived human progenitor cells. Haematologica 105(3):610–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatzeli L, Gaete M, Tucker AS (2017) Fgf10 and Sox9 are essential for the establishment of distal progenitor cells during mouse salivary gland development. Development 144(12):2294–2305

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen G, Yao C, Hasegawa T, Akamatsu T, Yoshimura H, Hosoi K (2014) Effects of isoproterenol on aquaporin 5 levels in the parotid gland of mice in vivo. Am J Physiol Endocrinol Metab 306(1):E100–E108

    Article  CAS  PubMed  Google Scholar 

  • Danielsson F, Peterson MK, Caldeira Araújo H, Lautenschläger F, Gad AKB (2018) Vimentin diversity in health and disease. Cell 7(10):147

    Article  CAS  Google Scholar 

  • Dawson L, Stanbury J, Venn N, Hasdimir B, Rogers S, Smith P (2006) Antimuscarinic antibodies in primary Sjögren’s syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells. Arthritis Rheum 54(4):1165–1173

    Article  CAS  PubMed  Google Scholar 

  • De Felice D, Alaimo A (2020) Mechanosensitive piezo channels in cancer: focus on altered calcium signaling in cancer cells and in tumor progression. Cancer 12(7):1780

    Article  Google Scholar 

  • Delporte C, Bryla A, Perret J (2016) Aquaporins in salivary glands: from basic research to clinical applications. Int j Mol Sci 17(2):166

    Article  PubMed  PubMed Central  Google Scholar 

  • Diegel CR, Cho KR, El-Naggar AK, Williams BO, Lindvall C (2010) Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of Apc and Pten in the mouse salivary gland: implications for human acinic cell carcinoma. Cancer Res 70(22):9143–9152

    Article  CAS  PubMed  Google Scholar 

  • Dmello C, Sawant S, Alam H, Gangadaran P, Mogre S, Tiwari R, D’Souza Z, Narkar M, Thorat R, Patil K (2017) Vimentin regulates differentiation switch via modulation of keratin 14 levels and their expression together correlates with poor prognosis in oral cancer patients. PLoS ONE 12(2):e0172559

    Article  PubMed  PubMed Central  Google Scholar 

  • Dmello C, Srivastava SS, Tiwari R, Chaudhari PR, Sawant S, Vaidya MM (2019) Multifaceted role of keratins in epithelial cell differentiation and transformation. J Biosci 44(2):33

    Article  PubMed  Google Scholar 

  • Ebeling G, Bläsche R, Hofmann F, Augstein A, Kasper M, Barth K (2014) Effect of P2X7 receptor knockout on AQP-5 expression of type I alveolar epithelial cells. PLoS ONE 9(6):e100282

    Article  PubMed  PubMed Central  Google Scholar 

  • Elliott KH, Millington G, Brugmann SA (2018) A novel role for cilia-dependent sonic hedgehog signaling during submandibular gland development. Dev Dyn 247(6):818–883

    Article  PubMed  PubMed Central  Google Scholar 

  • Emmerson E, May AJ, Nathan S, Cruz-Pacheco N, Lizama CO, Maliskova L, Zovein AC, Shen Y, Muench MO, Knox SM (2017) SOX2 regulates acinar cell development in the salivary gland. eLife 6:e26620

    Article  PubMed  PubMed Central  Google Scholar 

  • Ernstrom GG, Chalfie M (2002) Genetics of sensory mechanotransduction. Annu Rev Genet 36:411–453

    Article  CAS  PubMed  Google Scholar 

  • Fang X-Z, Zhou T, Xu J-Q, Wang Y-X, Sun M-M, He Y-J, Pan S-W, Xiong W, Peng Z-K, Gao X-H (2021) Structure, kinetic properties and biological function of mechanosensitive Piezo channels. Cell Biosci 11(1):13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fendrich V, Oh E, Bang S, Karikari C, Ottenhof N, Bisht S, Lauth M, Brossart P, Katsanis N, Maitra A (2011) Ectopic overexpression of Sonic Hedgehog (Shh) induces stromal expansion and metaplasia in the adult murine pancreas. Neoplasia 13(10):923–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiaschi M, Kolterud Å, Nilsson M, Toftgård R, Rozell B (2011) Targeted expression of GLI1 in the salivary glands results in an altered differentiation program and hyperplasia. Am J Pathol 179(5):2569–2579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbert S, Loranger A, Marceau N (2004) Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells. Mol Cell Biol 24(16):7072–7081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldman RD, Khuon S, Chou YH, Opal P, Steinert PM (1996) The function of intermediate filaments in cell shape and cytoskeletal integrity. J Cell Biol 134(4):971–983

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb PA, Bae C, Sachs F (2012) Gating the mechanical channel Piezo1: a comparison between whole-cell and patch recording. Channels 6(4):282–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan Z, Dong B, Huang C, Hu X, Zhang Y, Lin C (2019) Expression patterns of genes critical for SHH, BMP, and FGF pathways during the lumen formation of human salivary glands. J Mol Histol 50(3):217–227

    Article  CAS  PubMed  Google Scholar 

  • Gudipaty SA, Lindblom J, Loftus PD, Redd MJ, Edes K, Davey C, Krishnegowda V, Rosenblatt J (2017) Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543(7643):118–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Y, Liu C, Zhang D, Men H, Huo L, Geng Q, Wang S, Gao Y, Zhang W, Zhang Y (2019) Mechanosensitive ion channel Piezo1 promotes prostate cancer development through the activation of the Akt/mTOR pathway and acceleration of cell cycle. Int J Oncol 55(3):629–644

    CAS  PubMed  PubMed Central  Google Scholar 

  • He L, Si G, Huang J, Samuel AD, Perrimon N (2018) Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555(7694):103–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffman MP, Kibbey MC, Letterio JJ, Kleinman HK (1996) Role of laminin-1 and TGF-beta 3 in acinar differentiation of a human submandibular gland cell line (HSG). J Cell Sci 109(Pt 8):2013–2021

    Article  CAS  PubMed  Google Scholar 

  • Hoffman MP, Kidder BL, Steinberg ZL, Lakhani S, Ho S, Kleinman HK, Larsen M (2002) Gene expression profiles of mouse submandibular gland development: FGFR1 regulates branching morphogenesis in vitro through BMP-and FGF-dependent mechanisms. Development 129(24):5767–5778

    Article  CAS  PubMed  Google Scholar 

  • Hope JM, Lopez-Cavestany M, Wang W, Reinhart-King CA, King MR (2019) Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability. Cell Death Dis 10(11):837

    Article  PubMed  PubMed Central  Google Scholar 

  • Hung W-C, Yang JR, Yankaskas CL, Wong BS, Wu P-H, Pardo-Pastor C, Serra SA, Chiang M-J, Gu Z, Wirtz D (2016) Confinement sensing and signal optimization via Piezo1/PKA and myosin II pathways. Cell Rep 15(7):1430–1441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hyman A, Tumova S, Beech D (2017) Piezo1 channels in vascular development and the sensing of shear stress. Curr Top Membr 79:37–57

    Article  CAS  PubMed  Google Scholar 

  • Jaskoll T, Melnick M (1999) Submandibular gland morphogenesis: Stage-specific expression of TGF-α/EGF, IGF, TGF-β, TNF, and IL-6 signal transduction in normal embryonic mice and the phenotypic effects of TGF-β2, TGF-β3, and EGF-r null mutations. Anat Rec 256(3):252–268

    Article  CAS  PubMed  Google Scholar 

  • Jaskoll T, Zhou YM, Chai Y, Makarenkova HP, Collinson JM, West JD, Hajihosseini MK, Lee J, Melnick M (2002) Embryonic submandibular gland morphogenesis: stage-specific protein localization of FGFs, BMPs, Pax6 and Pax9 in normal mice and abnormal SMG phenotypes in FgfR2-IIIc+/Δ, BMP7–/–and Pax6–/–mice. Cells Tissues Organs 170(2–3):83–98

    Article  CAS  PubMed  Google Scholar 

  • Jaskoll T, Leo T, Witcher D, Ormestad M, Astorga J, Bringas P Jr, Carlsson P, Melnick M (2004) Sonic hedgehog signaling plays an essential role during embryonic salivary gland epithelial branching morphogenesis. Dev Dyn 229(4):722–732

    Article  CAS  PubMed  Google Scholar 

  • Jaskoll T, Abichaker G, Witcher D, Sala FG, Bellusci S, Hajihosseini MK, Melnick M (2005) FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. BMC Dev Biol 22(5):11

    Article  Google Scholar 

  • Kim S, Coulombe PA (2007) Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes Dev 21(13):1581–1597

    Article  CAS  PubMed  Google Scholar 

  • Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, Sedo A, Hyman AJ, McKeown L, Young RS, Yuldasheva NY, Majeed Y, Wilson LA, Rode B, Bailey MA, Kim HR, Fu Z, Carter DA, Bilton J, Imrie H, Ajuh P, Dear TN, Cubbon RM, Kearney MT, Prasad RK, Evans PC, Ainscough JF, Beech DJ (2014) Piezo1 integration of vascular architecture with physiological force. Nature 515(7526):279–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma S, Cahalan S, LaMonte G, Grubaugh ND, Zeng W, Murthy SE, Paytas E, Gamini R, Lukacs V, Whitwam T, Loud M, Lohia R, Berry L, Khan SM, Janse CJ, Bandell M, Schmedt C, Wengelnik K, Su AI, Honore E, Winzeler EA, Andersen KG, Patapoutian A (2018) Common PIEZO1 allele in African populations causes RBC dehydration and attenuates Plasmodium infection. Cell 173(2):443-455.e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto S, Kurimoto T, Taketo MM, Fujii S, Kikuchi A (2016) The WNT/MYB pathway suppresses KIT expression to control the timing of salivary proacinar differentiation and duct formation. Development 143(13):2311–2324

    CAS  PubMed  Google Scholar 

  • McHugh BJ, Murdoch A, Haslett C, Sethi T (2012) Loss of the integrin-activating transmembrane protein Fam38A (Piezo1) promotes a switch to a reduced integrin-dependent mode of cell migration. PLoS ONE 7(7):e40346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyazaki Y, Nakanishi Y, Hieda Y (2004) Tissue interaction mediated by neuregulin-1 and ErbB receptors regulates epithelial morphogenesis of mouse embryonic submandibular gland. Dev Dyn 230(4):591–596

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay S, Rohatgi R (2014) G-protein-coupled receptors, Hedgehog signaling and primary cilia. Semin Cell Dev Biol 33:63–72

    Article  CAS  PubMed  Google Scholar 

  • Murthy SE, Dubin AE, Patapoutian A (2017) Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat Rev Mol Cell Biol 18(12):771–783

    Article  CAS  PubMed  Google Scholar 

  • Neupane S, Sohn W-J, Gwon G-J, Kim K-R, Lee S, An C-H, Suh J-Y, Shin H-I, Yamamoto H, Cho S-W, Lee Y, Kim JY (2015) The role of APCDD1 in epithelial rearrangement in tooth morphogenesis. Histochem Cell Biol 144(4):377–387

    Article  CAS  PubMed  Google Scholar 

  • Neupane S, Adhikari N, Jung J-K, An C-H, Lee S, Jun J-H, Kim J-Y, Lee Y, Sohn W-J, Kim J-Y (2018) Regulation of mesenchymal signaling in palatal mucosa differentiation. Histochem Cell Biol 149(2):143–152

    Article  CAS  PubMed  Google Scholar 

  • Patel VN, Rebustini IT, Hoffman MP (2006) Salivary gland branching morphogenesis. Differentiation 74(7):349–364

    Article  CAS  PubMed  Google Scholar 

  • de Paula F, Teshima THN, Hsieh R, Souza MM, Nico MMS, Lourenco SV (2017) Overview of human salivary glands: highlights of morphology and developing processes. Anat Rec 300(7):1180–1188

    Article  Google Scholar 

  • Proctor GB (2016) The physiology of salivary secretion. Periodontology 70(1):11–25

    Article  Google Scholar 

  • Ranade SS, Qiu Z, Woo S-H, Hur SS, Murthy SE, Cahalan SM, Xu J, Mathur J, Bandell M, Coste B (2014) Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc Natl Acad Sci U S A 111(28):10347–10352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sisto M, Ribatti D, Lisi S (2022) E-Cadherin signaling in salivary gland development and autoimmunity. J Clin Med 11(8):2241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song Y, Chen J, Zhang C, Xin L, Li Q, Liu Y, Zhang C, Li S, Huang P (2022) Mechanosensitive channel Piezo1 induces cell apoptosis in pancreatic cancer by ultrasound with microbubbles. iScience 25(2):103733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart TA, Davis FM (2019) Formation and function of mammalian epithelia: roles for mechanosensitive PIEZO1 ion channels. Front Cell Dev Biol 7:260

    Article  PubMed  PubMed Central  Google Scholar 

  • Storz P (2017) Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 14(5):296–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun P, Yuan Y, Li A, Li B, Dai X (2010) Cytokeratin expression during mouse embryonic and early postnatal mammary gland development. Histochem Cell Biol 133(2):213–221

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Ogata K, Iwata J (2021) Cell signaling regulation in salivary gland development. Cell Mol Life Sci 78(7):3299–3315

    Article  CAS  PubMed  Google Scholar 

  • Teshima T, Wells K, Lourenço S, Tucker A (2016) Apoptosis in early salivary gland duct morphogenesis and lumen formation. J Dent Res 95(3):277–283

    Article  CAS  PubMed  Google Scholar 

  • Vining KH, Mooney DJ (2017) Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol 18(12):728–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Cao S, Arhatte M, Li D, Shi Y, Kurz S, Hu J, Wang L, Shao J, Atzberger A, Wang Z, Wang C, Zang W, Fleming I, Wettschureck N, Honoré E, Offermanns S (2020) Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice. Nat Commun 11(1):2303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Cheng G, Miao Y, Qiu F, Bai L, Gao Z, Huang Y, Dong L, Niu X, Wang X (2021) Piezo type mechanosensitive ion channel component 1 facilitates gastric cancer omentum metastasis. J Cell Mol Med 25(4):2238–2253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu J, Lewis AH, Grandl J (2017) Touch, tension, and transduction—the function and regulation of Piezo ion channels. Trends Biochem Sci 42(1):57–71

    Article  PubMed  Google Scholar 

  • Xie J, Yao B, Han Y, Shang T, Gao D, Yang S, Ma K, Huang S, Fu X (2015) Cytokeratin expression at different stages in sweat gland development of C57BL/6J mice. Int J Extrem Wounds 14(4):365–371

    Article  CAS  Google Scholar 

  • Yang Y-L, Liu Y-S, Chuang L-Y, Guh J-Y, Lee T-C, Liao T-N, Hung M-Y, Chiang T-A (2009) Bone morphogenetic protein-2 antagonizes renal interstitial fibrosis by promoting catabolism of type I transforming growth factor-β receptors. Endocrinology 150(2):727–740

    Article  CAS  PubMed  Google Scholar 

  • Yatsuki K, Ryo E, Morita M, Seto M, Kamata H, Yonaga Y (2021) Correlation between newborn size and gross fetal movement as counted by a fetal movement acceleration measurement recorder. J Dev Orig Health Dis 12(3):452–455

    Article  PubMed  Google Scholar 

  • Zhang X, Yun JS, Han D, Yook JI, Kim HS, Cho ES (2020) TGF-β pathway in salivary gland fibrosis. Int J Mol Sci 21(23):9138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu B, Qian W, Han C, Bai T, Hou X (2021) Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis. Mol Ther Nucleic Acids 24:241–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the National Research Foundation of Korea (grant nos. NRF-2019R1I1A3A01062091 and NRF-2022R1I1A2063745) and is funded by the Ministry of Education, Science, and Technology, South Korea.

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P.E., K.J.Y., and J.J.K. contributed to conception, design, data acquisition, analysis, and interpretation. The authors also drafted and critically revised the manuscript. A.Y.P., K.T.Y., K.A., K.J.Y., Y.H., C.S.W., and S.W.J. contributed to the conception, analysis, and critical review of the manuscript. All authors gave their final approval and agreed to be accountable for all aspects of this work.

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Correspondence to Jae-Young Kim or Jae-Kwang Jung.

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Pokharel, E., Aryal, Y.P., Kim, TY. et al. Developmental function of Piezo1 in mouse submandibular gland morphogenesis. Histochem Cell Biol 159, 477–487 (2023). https://doi.org/10.1007/s00418-023-02181-w

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