Abstract
Telocytes (TCs) are CD34-positive interstitial cells that have long cytoplasmic projections, called telopodes; they have been identified in several organs and in various species. These cells establish a complex communication network between different stromal and epithelial cell types, and there is growing evidence that they play a key role in physiology and pathology. In many tissues, TC network impairment has been implicated in the onset and progression of pathological conditions, which makes the study of TCs of great interest for the development of novel therapies. In this review, we summarise the main methods involved in the characterisation of these cells as well as their inherent difficulties and then discuss the functional assays that are used to uncover the role of TCs in normal and pathological conditions, from the most traditional to the most recent. Furthermore, we provide future perspectives in the study of TCs, especially regarding the establishment of more precise markers, commercial lineages and means for drug delivery and genetic editing that directly target TCs.
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Abbreviations
- ApoE:
-
Apolipoprotein E
- BMP4:
-
Bone morphogenetic protein 4
- CAVD:
-
Calcific aortic valve disease
- CD31:
-
Cluster of differentiation 31
- CD34:
-
Cluster of differentiation 34
- CD81:
-
Cluster of differentiation 81
- CD90:
-
Cluster of differentiation 90
- Cdip1:
-
Cell death inducing p53 target 1
- CREB1:
-
CAMP response element binding protein 1
- CRISPR-Cas9:
-
Clustered regularly interspaced short palindromic repeats–CRISPR associated protein 9
- CSCs:
-
Cardiac stem cells
- CTGF:
-
Connective tissue growth factor
- Dkk3:
-
Dickkopf-related protein 3
- DUOX2:
-
Dual oxidase 2
- ECM:
-
Extracellular matrix
- EGF:
-
Epidermal growth factor
- EVs:
-
Extracellular vesicles
- Foxl1:
-
Forkhead box L1
- HCC:
-
Hepatocellular carcinoma
- HGF:
-
Hepatocyte growth factor
- IL-6:
-
Interleukin 6
- lncRNA:
-
Long noncoding RNA
- LPS:
-
Lipopolysaccharide
- MCP-1:
-
Monocyte chemoattractant protein-1
- MHY14:
-
Myosin heavy chain 14
- MIP-1α:
-
Macrophage inflammatory protein 1α
- MIP-2:
-
Macrophage inflammatory protein-2
- miR-146a-5p:
-
MicroRNA 146a-5p
- miRNA-21-5p:
-
MicroRNA 21-5p
- miR-942-3p:
-
MicroRNA 942-3p
- MMP9:
-
Matrix metalloproteinase 9
- MSCs:
-
Mesenchymal stem cells
- MYL9:
-
Myosin regulatory light polypeptide 9
- MyoD:
-
Myoblast determination protein 1
- Pax7:
-
Paired box protein 7
- PDGFβ:
-
Platelet-derived growth factor subunit β
- PDGFRα:
-
Platelet-derived growth factor receptor α
- PDGFRβ:
-
Platelet-derived growth factor receptor β
- qPCR:
-
Quantitative polymerase chain reaction
- Rosa-mTmG:
-
ROSA26-membrane-tdT-membrane-EGFP
- scRNA-seq:
-
Single-cell RNA sequencing
- SDF-1:
-
Stromal cell-derived factor 1
- SEM:
-
Scanning electron microscopy
- sFRP1:
-
Secreted Frizzled-related protein 1
- SNHG16:
-
Small nucleolar RNA host gene 16
- SPRR1A:
-
Small proline-rich repeat protein 1A
- TAGLN:
-
Transgelin
- TC:
-
Telocyte
- TEM:
-
Transmission electron microscopy
- TGFβ1:
-
Transforming growth factor β1
- TP:
-
Telopode
- VEGF:
-
Vascular endothelial growth factor
- Wnt:
-
Wingless-related integration site
References
Abd-Elhafeez HH, Abdo W, Kamal BM, Soliman SA (2020) Fish TCs and their relation to rodlet cells in ruby-red-fin shark (rainbow shark) Epalzeorhynchos frenatum (Teleostei: Cyprinidae). Sci Rep 10(1):18907. https://doi.org/10.1038/s41598-020-75677-3
Abdel-Maksoud FM, Abd-Elhafeez HH, Soliman SA (2019) Morphological changes of TCs in camel efferent ductules in response to seasonal variations during the reproductive cycle. Sci Rep 9(1):4507. https://doi.org/10.1038/s41598-019-41143-y
Albulescu R, Tanase C, Codrici E, Popescu DI, Cretoiu SM, Popescu LM (2015) The secretome of myocardial TCs modulates the activity of cardiac stem cells. J Cell Mol Med 19(8):1783–1794. https://doi.org/10.1111/jcmm.12624
Aleksandrovych V, Walocha JA, Gil K (2016) TCs in female reproductive system (human and animal). J Cell Mol Med 20(6):994–1000. https://doi.org/10.1111/jcmm.12843
Aschacher T, Aschacher O, Schmidt K, Enzmann FK, Eichmair E, Winkler B, Arnold Z, Nagel F, Podesser BK, Mitterbauer A, Messner B, Grabenwöger M, Laufer G, Ehrlich MP, Bergmann M (2022) The role of TCs and TC-derived exosomes in the development of thoracic aortic aneurysm. Int J Mol Sci 23(9):4730. https://doi.org/10.3390/ijms23094730.PMID:35563123;PMCID:PMC9099883
Awad M, Ghanem ME (2018) Localization of TCs in rabbits testis: histological and immunohistochemical approach. Microsc Res Tech 81(11):1268–1274. https://doi.org/10.1002/jemt.23133
Banciu DD, Crețoiu D, Crețoiu SM, Banciu A, Popa D, David R, Berghea-Neamtu CS, Cipaian CR, Negrea MO, Gheonea M, Neamtu B (2022) TCs’ role in modulating gut motility function and development: medical hypotheses and literature review. Int J Mol Sci 23(13):7017. https://doi.org/10.3390/ijms23137017
Bani D, Formigli L, Gherghiceanu M, Faussone-Pellegrini MS (2010) TCs as supporting cells for myocardial tissue organization in developing and adult heart. J Cell Mol Med 14(10):2531–2538. https://doi.org/10.1111/j.1582-4934.2010.01119.x
Bei Y, Zhou Q, Fu S et al (2015) Cardiac TCs and fibroblasts in primary culture: different morphologies and immunophenotypes. PLoS One 10:e0115991. https://doi.org/10.1371/journal.pone.0115991
Canella M, Nalick S, Corem N, Gharbi A, Ben-Porath I, Shoshkes-Carmel M (2023) TCs are a critical source of Wnts essential for hair follicle regeneration. BioRxiv. https://doi.org/10.1101/2023.05.17.541070
Ceafalan L, Gherghiceanu M, Popescu LM, Simionescu O (2012) TCs in human skin–are they involved in skin regeneration? J Cell Mol Med 16(7):1405–1420. https://doi.org/10.1111/j.1582-4934.2012.01580.x
Chen X, Zeng J, Huang Y, Gong M, Ye Y, Zhao H, Chen Z, Zhang H (2021) TCs and their structural relationships with surrounding cell types in the skin of silky fowl by immunohistochemistrical, transmission electron microscopical and morphometric analysis. Poult Sci 100(9):101367. https://doi.org/10.1016/j.psj.2021.101367
Chen Z, Zhang N, Chu HY, Yu Y, Zhang ZK, Zhang G, Zhang BT (2020) Connective tissue growth factor: from molecular understandings to drug discovery. Front Cell Dev Biol 29(8):593269. https://doi.org/10.3389/fcell.2020.593269
Clarke J (2020) PDGF-BB is the key to unlocking pathological angiogenesis in OA. Nat Rev Rheumatol 16(6):298. https://doi.org/10.1038/s41584-020-0423-3
Cretoiu D, Vannucchi MG, Bei Y et al (2019) TCs: new connecting devices in the stromal space of organs. In (Ed.), Innovations in Cell Research and Therapy. IntechOpen. https://doi.org/10.5772/intechopen.89383
Cretoiu SM, Cretoiu D, Popescu LM (2012) Human myometrium - the ultrastructural 3D network of TCs. J Cell Mol Med 16(11):2844–2849. https://doi.org/10.1111/j.1582-4934.2012.01651
Cretoiu D, Gherghiceanu M, Hummel E, Zimmermann H, Simionescu O, Popescu LM (2015) FIB-SEM tomography of human skin TCs and their extracellular vesicles. J Cell Mol Med 19(4):714–722. https://doi.org/10.1111/jcmm.12578
Cretoiu D, Xu J, Xiao J, Cretoiu SM (2016) TCs and their extracellular vesicles-evidence and hypotheses. Int J Mol Sci 17(8):1322. https://doi.org/10.3390/ijms17081322
Cretoiu SM, Popescu LM (2014) TCs revisited. Biomol Concepts 5(5):353–369. https://doi.org/10.1515/bmc-2014-0029
Cui Z, Wu H, Xiao Y, Xu T, Jia J, Lin H, Lin R, Chen K, Lin Y, Li K, Wu X, Li C, Yu B (2022) Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation. Bone Res 10(1):58. https://doi.org/10.1038/s41413-022-00229-6
De Paula JC, Doello K, Mesas C, Kapravelou G, Cornet-Gómez A, Orantes FJ, Martínez R, Linares F, Prados JC, Porres JM, Osuna A, de Pablos LM (2022) Exploring honeybee abdominal anatomy through micro-CT and novel multi-staining approaches. InSects 13(6):556. https://doi.org/10.3390/insects13060556
Díaz-Flores L, Gutiérrez R, García MP, Gayoso S, Gutiérrez E, Díaz-Flores L Jr, Carrasco JL (2020) TCs in the normal and pathological peripheral nervous system. Int J Mol Sci 21(12):4320. https://doi.org/10.3390/ijms21124320
Díaz-Flores L, Gutiérrez R, García MP, González-Gómez M, Rodríguez-Rodriguez R, Hernández-León N, Díaz-Flores L Jr, Carrasco JL (2021) Cd34+ Stromal cells/TCs in normal and pathological skin. Int J Mol Sci 22(14):7342. https://doi.org/10.3390/ijms22147342
Donaudy F, Snoeckx R, Pfister M, Zenner HP, Blin N, Di Stazio M, Ferrara A, Lanzara C, Ficarella R, Declau F, Pusch CM, Nürnberg P, Melchionda S, Zelante L, Ballana E, Estivill X, Van Camp G, Gasparini P, Savoia A (2004) Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am J Hum Genet 74(4):770–776. https://doi.org/10.1086/383285
Elmentaite R, Ross ADB, Roberts K, James KR, Ortmann D, Gomes T, Nayak K, Tuck L, Pritchard S, Bayraktar OA, Heuschkel R, Vallier L, Teichmann SA, Zilbauer M (2020) Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease. Dev Cell 55(6):771-783.e5. https://doi.org/10.1016/j.devcel.2020.11.010
Felisbino SL, Sanches BDA, Delella FK, Scarano WR, Dos Santos FCA, Vilamaior PSL, Taboga SR, Justulin LA (2019) Prostate TCs change their phenotype in response to castration or testosterone replacement. Sci Rep 9(1):3761. https://doi.org/10.1038/s41598-019-40465-1
Forghani A, Koduru SV, Chen C, Leberfinger AN, Ravnic DJ, Hayes DJ (2020) Differentiation of Adipose Tissue-Derived CD34+/CD31- Cells into endothelial cells in vitro. Regen Eng Transl Med 6(1):101–110. https://doi.org/10.1007/s40883-019-00093-7. Epub 2019 Mar 15. PMID: 33344757; PMCID: PMC7747864
Friedman MS, Oyserman SM, Hankenson KD (2009) Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. J Biol Chem 284(21):14117–14125. https://doi.org/10.1074/jbc.M808337200
Fries KM, Blieden T, Looney RJ, Sempowski GD, Silvera MR, Willis RA, Phipps RP (1994) Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis. Clin Immunol Immunopathol 72(3):283–292. https://doi.org/10.1006/clin.1994.1144
Gao F, Li C, Danopoulos S, Al Alam D, Peinado N, Webster S, Borok Z, Kohbodi GA, Bellusci S, Minoo P (2022) Hedgehog-responsive PDGFRa(+) fibroblasts maintain a unique pool of alveolar epithelial progenitor cells during alveologenesis. Cell Rep 39(1):110608. https://doi.org/10.1016/j.celrep.2022.110608
Gauthier V, Kyriazi M, Nefla M, Pucino V, Raza K, Buckley CD, Alsaleh G (2023) Fibroblast heterogeneity: keystone of tissue homeostasis and pathology in inflammation and ageing. Front Immunol 28(14):1137659. https://doi.org/10.3389/fimmu.2023.1137659
Gherghiceanu M, Popescu LM (2012) Cardiac TCs - their junctions and functional implications. Cell Tissue Res 348(2):265–279. https://doi.org/10.1007/s00441-012-1333-8
Herrmann IK, Wood MJA, Fuhrmann G (2021) Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol 16(7):748–759. https://doi.org/10.1038/s41565-021-00931-2. Epub 2021 Jul 1 PMID: 34211166
Holloway EM, Czerwinski M, Tsai YH, Wu JH, Wu A, Childs CJ, Walton KD, Sweet CW, Yu Q, Glass I, Treutlein B, Camp JG, Spence JR (2021) Mapping development of the human intestinal niche at single-cell resolution. Cell Stem Cell 28(3):568-580.e4. https://doi.org/10.1016/j.stem.2020.11.008
Huang YL, Zhang FL, Tang XL, Yang XJ (2021) TCs enhances M1 differentiation and phagocytosis while inhibits mitochondria-mediated apoptosis via activation of NF-κB in macrophages. Cell Transplant 30:9636897211002762. https://doi.org/10.1177/09636897211002762
Hussein MT, Abdel-Maksoud FM (2020) structural investigation of epididymal microvasculature and its relation to TCs and immune cells in camel. Microsc Microanal 26(5):1024–1034. https://doi.org/10.1017/S1431927620001786
Hussein M, Mokhtar DM (2018) The roles of telocytes in lung development and angiogenesis: an immunohistochemical, ultrastructural, scanning electron microscopy and morphometrical study. Dev Biol 443:137–152. https://doi.org/10.1016/j.ydbio.2018.09.010
Hutter-Schmid B, Humpel C (2016) Platelet-derived growth factor receptor-beta is differentially regulated in primary mouse pericytes and brain slices. Curr Neurovasc Res 13(2):127–134. https://doi.org/10.2174/1567202613666160219120411
Iyadurai S, Arnold WD, Kissel JT, Ruhno C, Mcgovern VL, Snyder PJ, Prior TW, Roggenbuck J, Burghes AH, Kolb SJ (2017) Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family. Muscle Nerve 56(2):341–345. https://doi.org/10.1002/mus.25491
Jiang XJ, Cretoiu D, Shen ZJ, Yang XJ (2018) An in vitro investigation of TCs-educated macrophages: morphology, heterocellular junctions, apoptosis and invasion analysis. J Transl Med 16(1):85. https://doi.org/10.1186/s12967-018-1457-z
Kaestner KH (2019) The intestinal stem cell niche: a central role for Foxl1-expressing subepithelial TCs. Cell Mol Gastroenterol Hepatol 8(1):111–117. https://doi.org/10.1016/j.jcmgh.2019.04.001
Klein M, Csöbönyeiová M, Danišovič Ľ, Lapides L, Varga I (2022) TCs in the female reproductive system: up-to-date knowledge, challenges and possible clinical applications. Life (basel) 12(2):267. https://doi.org/10.3390/life12020267
Kolev HM, Tian Y, KIM MS, Leu NA, Adams-Tzivelekidis AS, Lengner CJ, Li N, Kaestner KH, (2021) A FoxL1-CreERT-2AtdTomado mouse labels subepithelial telocytes. Cell Mol Gastroenterol Hepatol 12:11155–1158
Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S (2012) TGF-β - an excellent servant but a bad master. J Transl Med 3(10):183. https://doi.org/10.1186/1479-5876-10-183
Kuwabara JT, Hara A, Bhutada S, Gojanovich GS, Chen J, Hokutan K, Shettigar V, Lee AY, DeAngelo LP, Heckl JR, Jahansooz JR, Tacdol DK, Ziolo MT, Apte SS, Tallquist MD (2022) Consequences of PDGFRα+ fibroblast reduction in adult murine hearts. Elife 23(11):e69854. https://doi.org/10.7554/eLife.69854
Lekic PC, Pender N, McCulloch CA (1997) Is fibroblast heterogeneity relevant to the health, diseases, and treatments of periodontal tissues? Crit Rev Oral Biol Med 8(3):253–268. https://doi.org/10.1177/10454411970080030201
Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C (1994) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8(16):1875–1887. https://doi.org/10.1101/gad.8.16.1875
Liang Y, Wang S, An T, Tarique I, Vistro WA, Liu Y, Wang Z, Zhang H, Shi Y, Haseeb A, Gandahi NS, Iqba A, Yang H, Chen Q, Yang P (2019) TCs as a novel structural component in the muscle layers of the goat rumen. Cell Transplant 28(7):955–966. https://doi.org/10.1177/0963689719842514
Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, Hintze M, Pu Q, Yuan Z, Lv L, Chen H, Lai B, Feng S, Qi X, Cai D (2021) Cardiac TCs inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics 11(1):268–291. https://doi.org/10.7150/thno.47021.PMID:33391474;PMCID:PMC7681094
Li H, Lu S, Liu H, Ge J, Zhang H (2014) Scanning electron microscope evidence of TCs in vasculature. J Cell Mol Med 18(7):1486–1489. https://doi.org/10.1111/jcmm.12333
Lorincz A, Redelman D, Horváth VJ, Bardsley MR, Chen H, Ordög T (2008) Progenitors of interstitial cells of Cajal in the postnatal murine stomach. Gastroenterology 134(4):1083–1093. https://doi.org/10.1053/j.gastro.2008.01.036
Luesma MJ, Cantarero I, Sánchez-Cano AI, Rodellar C, Junquera C (2021) Ultrastructural evidence for TCs in equine tendon. J Anat 238(3):527–535. https://doi.org/10.1111/joa.13335. Epub 2020 Oct 18. PMID: 33070316; PMCID: PMC7855077
Lv L, Liao Z, Luo J, Chen H, Guo H, Yang J, Huang R, Pu Q, Zhao H, Yuan Z, Feng S, Qi X, Cai D (2020) Cardiac TCs exist in the adult Xenopus tropicalis heart. J Cell Mol Med 24(4):2531–2541. https://doi.org/10.1111/jcmm.14947
Lynch MD, Watt FM (2018) Fibroblast heterogeneity: implications for human disease. J Clin Invest 128(1):26–35. https://doi.org/10.1172/JCI93555. Epub 2018 Jan 2. PMID: 29293096; PMCID: PMC5749540
Maldarine JS, Sanches BDA, Santos VA, Góes RM, Vilamaior PSL, Carvalho HF, Taboga SR (2022) The complex role of TCs in female prostate tumorigenesis in a rodent model. Cell Biol Int 46(9):1495–1509. https://doi.org/10.1002/cbin.11816
Manetti M, Guiducci S, Ruffo M, Rosa I, Faussone-Pellegrini MS, Matucci-Cerinic M, Ibba-Manneschi L (2013) Evidence for progressive reduction and loss of TCs in the dermal cellular network of systemic sclerosis. J Cell Mol Med 17(4):482–496. https://doi.org/10.1111/jcmm.12028
Manetti M, Rosa I, Messerini L, Guiducci S, Matucci-Cerinic M, Ibba-Manneschi L (2014) A loss of TCs accompanies fibrosis of multiple organs in systemic sclerosis. J Cell Mol Med 18(2):253–262. https://doi.org/10.1111/jcmm.12228
Manetti M, Tani A, Rosa I, Chellini F, Squecco R, Idrizaj E, Zecchi-Orlandini S, Ibba-Manneschi L, Sassoli C (2019) Morphological evidence for TCs as stromal cells supporting satellite cell activation in eccentric contraction-induced skeletal muscle injury. Sci Rep 9(1):14515. https://doi.org/10.1038/s41598-019-51078-z
Man K, Brunet MY, Fernandez-Rhodes M, Williams S, Heaney LM, Gethings LA, Federici A, Davies OG, Hoey D, Cox SC (2021) Epigenetic reprogramming enhances the therapeutic efficacy of osteoblast-derived extracellular vesicles to promote human bone marrow stem cell osteogenic differentiation. J Extracell Vesicles 10(9):e12118. https://doi.org/10.1002/jev2.12118. Epub 2021 Jul 7. PMID: 34262674; PMCID: PMC8263905
Manole CG, Gherghiceanu M, Ceafalan LC, Hinescu ME (2022) Dermal TCs: A Different Viewpoint of Skin Repairing and Regeneration. Cells 11(23):3903. https://doi.org/10.3390/cells11233903
Marini M, Rosa I, Guasti D, Gacci M, Sgambati E, Ibba-Manneschi L, Manetti M (2018) Reappraising the microscopic anatomy of human testis: identification of TC networks in the peritubular and intertubular stromal space. Sci Rep 8(1):14780. https://doi.org/10.1038/s41598-018-33126-2
Marini M, Ibba-Manneschi L, Rosa I, Sgambati E, Manetti M (2019) Changes in the TC/CD34+ stromal cell and α-SMA+ myoid cell networks in human testicular seminoma. Acta Histochem 121(8):151442. https://doi.org/10.1016/j.acthis.2019.151442
McCarthy N, Manieri E, Storm EE, Saadatpour A, Luoma AM, Kapoor VN, Madha S, Gaynor LT, Cox C, Keerthivasan S, Wucherpfennig K, Yuan GC, de Sauvage FJ, Turley SJ, Shivdasani RA (2020) Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26(3):391-402.e5. https://doi.org/10.1016/j.stem.2020.01.008. Epub 2020 Feb 20. PMID: 32084389; PMCID: PMC7412576
Meng X, Ding B, Zhu Z, Ma Q, Wang Q, Feng Y, Liu Y, Wang J, Yang P (2022) Evaluation of the plasticity of novel regulatory cells-TCs-in the gonad of the male Chinese soft-shelled turtle (Pelodiscus sinensis) associated with seasonal reproductive activity. Microsc Microanal 7:1–9. https://doi.org/10.1017/S1431927622012302
Niculite CM, Regalia TM, Gherghiceanu M, Huica R, Surcel M, Ursaciuc C, Leabu M, Popescu LM (2015) Dynamics of telopodes (TC prolongations) in cell culture depends on extracellular matrix protein. Mol Cell Biochem 398(1–2):157–164. https://doi.org/10.1007/s11010-014-2215-z
Ouko L, Ziegler TR, Gu LH, Eisenberg LM, Yang VW (2004) Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells. J Biol Chem 279(25):26707–26715. https://doi.org/10.1074/jbc.M402877200
Pakula H, Omar M, Carelli R, Pederzoli F, Fanelli GN, Pannellini T, Van Emmenis L, Rodrigues S, Fidalgo-Ribeiro C, Nuzzo PV, Brady NJ, Jere M, Unkenholz C, Alexanderani MK, Khani F, de Almeida FN, Abate-Shen C, Greenblatt MB, Rickman DS, Barbieri CE, Robinson BD, Marchionni L, Loda M (2023) Distinct mesenchymal cell states mediate prostate cancer progression. bioRxiv [Preprint]. https://doi.org/10.1101/2023.03.29.534769
Pimentel Neto J, Rocha LC, Barbosa GK, Jacob CDS, Krause Neto W, Watanabe IS, Ciena AP (2020) Myotendinous junction adaptations to ladder-based resistance training: identification of a new TC niche. Sci Rep 10(1):14124. https://doi.org/10.1038/s41598-020-70971-6
Pomerleau V, Nicolas VR, Jurkovic CM, Faucheux N, Lauzon MA, Boisvert FM, Perreault N (2023) FOXL1+ TCs in mouse colon orchestrate extracellular matrix biodynamics and wound repair resolution. J Proteomics 16(271):104755. https://doi.org/10.1016/j.jprot.2022.104755
Popescu LM, Manole E, Serboiu CS, Manole CG, Suciu LC, Gherghiceanu M, Popescu BO (2011) Identification of TCs in skeletal muscle interstitium: implication for muscle regeneration. J Cell Mol Med 15(6):1379–1392. https://doi.org/10.1111/j.1582-4934.2011.01330.x
Popescu LM, Faussone-Pellegrini MS (2010) TCS - a case of serendipity: the winding way from interstitial cells of Cajal (ICC), via interstitial Cajal-like cells (ICLC) to TCS. J Cell Mol Med 14:729–740. https://doi.org/10.1111/j.1582-4934.2010.01059.x
Pulze L, Baranzini N, Girardello R, Grimaldi A, Ibba-Manneschi L, Ottaviani E, Reguzzoni M, Tettamanti G, de Eguileor M (2017) A new cellular type in invertebrates: first evidence of TCs in leech Hirudo medicinalis. Sci Rep 7(1):13580. https://doi.org/10.1038/s41598-017-13202-9
Qi G, Lin M, Xu M, Manole CG, Wang X, Zhu T (2012) TCs in the human kidney cortex. J Cell Mol Med 16(12):3116–3122. https://doi.org/10.1111/j.1582-4934.2012.01582.x
Ramazani Y, Knops N, Elmonem MA, Nguyen TQ, Arcolino FO, van den Heuvel L, Levtchenko E, Kuypers D, Goldschmeding R (2018) Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 68–69:44–66. https://doi.org/10.1016/j.matbio.2018.03.007
Ravalli S, Federico C, Lauretta G, Saccone S, Pricoco E, Roggio F, Di Rosa M, Maugeri G, Musumeci G (2021) Morphological evidence of TCs in skeletal muscle interstitium of exercised and sedentary rodents. Biomedicines 9(7):807. https://doi.org/10.3390/biomedicines9070807
Romano E, Rosa I, Fioretto BS, Lucattelli E, Innocenti M, Ibba-Manneschi L, Matucci-Cerinic M, Manetti M (2020) A Two-step immunomagnetic microbead-based method for the isolation of human primary skin TCs/CD34+ stromal cells. Int J Mol Sci 21(16):5877. https://doi.org/10.3390/ijms21165877
Rosa I, Marini M, Guasti D, Ibba-Manneschi L, Manetti M (2018) Morphological evidence of TCs in human synovium. Sci Rep 8(1):3581. https://doi.org/10.1038/s41598-018-22067-5
Rosa I, Taverna C, Novelli L, Marini M, Ibba-Manneschi L, Manetti M (2019) TCs constitute a widespread interstitial meshwork in the lamina propria and underlying striated muscle of human tongue. Sci Rep 9(1):5858. https://doi.org/10.1038/s41598-019-42415-3
Rosa I, Romano E, Fioretto BS, Guasti D, Ibba-Manneschi L, Matucci-Cerinic M, Manetti M (2021) Scleroderma-like impairment in the network of TCs/CD34+ stromal cells in the experimental mouse model of bleomycin-induced dermal fibrosis. Int J Mol Sci 22:12407
Rusu MC, Mirancea N, Mănoiu VS, Vâlcu M, Nicolescu MI, Păduraru D (2012) Skin TCs. Ann Anat 194(4):359–367. https://doi.org/10.1016/j.aanat.2011.11.007
Rusu MC, Loreto C, Mănoiu VS (2014) Network of TCs in the temporomandibular joint disc of rats. Acta Histochem 116(4):663–668. https://doi.org/10.1016/j.acthis.2013.12.005
Sackett SD, Fulmer JT, Friedman JR, Kaestner KH (2007) Foxl1-Cre BAC transgenic mice: a new tool for gene ablation in the gastrointestinal mesenchyme. Genesis 45:518–522. https://doi.org/10.1002/dvg.20315
Sanches BDA, Maldarine JDS, Tamarindo GH, Da Silva ADT, Lima MLD, Rahal P, Góes RM, Taboga SR, Carvalho HF (2020a) Explant culture: a relevant tool for the study of TCs. Cell Biol Int 44(12):2395–2408. https://doi.org/10.1002/cbin.11446
Sanches BDA, Maldarine JS, Vilamaior PSL, Felisbino SL, Carvalho HF, Taboga SR (2021a) Stromal cell interplay in prostate development, physiology, and pathological conditions. Prostate 81(13):926–937. https://doi.org/10.1002/pros.24196
Sanches BDA, Maldarine JS, Zani BC, Tamarindo GH, Biancardi MF, Santos FCA, Rahal P, Góes RM, Felisbino SL, Vilamaior PSL, Taboga SR (2017) TCs play a key role in prostate tissue organisation during the gland morphogenesis. J Cell Mol Med 21(12):3309–3321. https://doi.org/10.1111/jcmm.13234
Sanches BDA, Tamarindo GH, Dos Santos MJ, da Silva ADT, Dos Santos VA, Lima MLD, Rahal P, Góes RM, Taboga SR, Felisbino SL, Carvalho HF (2020b) TCs contribute to aging-related modifications in the prostate. Sci Rep 10(1):21392. https://doi.org/10.1038/s41598-020-78532-7
Sanches BDA, Tamarindo GH, Maldarine JDS, Da Silva ADT, Dos Santos VA, Góes RM, Taboga SR, Carvalho HF (2021b) TCs of the male urogenital system: interrelationships, possible functions, and pathological implications. Cell Biol Int 45(8):1613–1623. https://doi.org/10.1002/cbin.11612
Sanches BDA, Tamarindo GH, da Silva ADT, Amaro GM, Dos Santos Maldarine J, Dos Santos VA, Guerra LHA, Baraldi CMB, Góes RM, Taboga SR, Carvalho HF (2023) Stromal cell-derived factor 1 (SDF-1) increases the number of TCs in ex vivo and in vitro assays. Histochem Cell Biol. https://doi.org/10.1007/s00418-023-02223-3. Epub ahead of print. PMID: 37474667
Shoshkes-Carmel M, Wang YJ, Wangensteen KJ, Tóth B, Kondo A, Massasa EE, Itzkovitz S, Kaestner KH (2018) Subepithelial TCs are an important source of Wnts that supports intestinal crypts. Nature 557(7704):242–246. https://doi.org/10.1038/s41586-018-0084-4. Epub 2018 May 2. Erratum in: Nature. 2018 Aug;560(7718):E29. PMID: 29720649; PMCID: PMC5966331
Soliman S (2017a) Potential role of telocytes in development of embryonic ganglia. SF J Stem Cells 1:1
Soliman SMA, Emeish WFA (2017b) Morphological alternations of intraepithelial and stromal TCs in response to salinity challenges. BioRxiv. https://doi.org/10.1101/115881
Song D, Xu M, Qi R et al (2019) Influence of gene modification in biological behaviors and responses of mouse lung TCs to inflammation. J Transl Med 17:158. https://doi.org/10.1186/s12967-019-1870-y
Suciu LC, Popescu BO, Kostin S, Popescu LM (2012) Platelet-derived growth factor receptor-β-positive TCs in skeletal muscle interstitium. J Cell Mol Med 16(4):701–707. https://doi.org/10.1111/j.1582-4934.2011.01505.x
Tamura Y, Takata K, Eguchi A, Maeda M, Kataoka Y (2021) Age-related changes in NG2-expressing TCs of rat stomach. PLoS ONE 16(4):e0249729. https://doi.org/10.1371/journal.pone.0249729
Tan YZ, Wang HJ, Zhang MH, Quan Z, Li T, He QZ (2014) CD34+ VEGFR-3+ progenitor cells have a potential to differentiate towards lymphatic endothelial cells. J Cell Mol Med 18(3):422–433. https://doi.org/10.1111/jcmm.12233
Tang H, Liang T, Zhou Y, Ju H, Song D, Fang H (2022) TCs reduce oxidative stress by downregulating DUOX2 expression in inflamed lungs of mice. Acta Biochim Biophys Sin (shanghai) 54(4):574–582. https://doi.org/10.3724/abbs.2022017
Tang L, Song D, Qi R, Zhu B, Wang X (2023) Roles of pulmonary TCs in airway epithelia to benefit experimental acute lung injury through production of TC-driven mediators and exosomes. Cell Biol Toxicol 39(2):451–465. https://doi.org/10.1007/s10565-021-09670-5
Tay H, Vandecasteele T, Van den Broeck W (2017) Identification of TCs in the porcine heart. Anat Histol Embryol 46(6):519–527. https://doi.org/10.1111/ahe.12296
Traini C, Faussone-Pellegrini Guasti D, Popolo GD, Frizzi J, Serni S, Vannucchi MG (2018) Adaptiva changes of telocytes in the urinary bladder of patients affected by neurogenic detrusor overactivity. J Cell Mol Med 22:195–206
Toader OD, Rusu MC, Mogoantă L, Hostiuc S, Jianu AM, Ilie AC (2019) An immunohistochemical study of gastric mucosa and critical review indicate that the subepithelial TCs are prelymphatic endothelial cells. Medicina (kaunas) 55(7):316. https://doi.org/10.3390/medicina55070316
Touma M, Kang X, Gao F, Zhao Y, Cass AA, Biniwale R, Xiao X, Eghbali M, Coppola G, Reemtsen B, Wang Y (2017) Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight 2(17):e94904. https://doi.org/10.1172/jci.insight.94904
Van Niel G, D’Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19(4):213–228. https://doi.org/10.1038/nrm.2017.125. Epub 2018 Jan 17 PMID: 29339798
Vannucchi MG, Traini C (2016) Interstitial cells of Cajal and TCs in the gut: twins, related or simply neighbor cells? Biomol Concepts 7(2):93–102. https://doi.org/10.1515/bmc-2015-0034
Vannucchi MG, Traini C, Manetti M, Ibba-Manneschi L, Faussone-Pellegrini MS (2013) TCs express PDGFRα in the human gastrointestinal tract. J Cell Mol Med 17(9):1099–1108. https://doi.org/10.1111/jcmm.12134
Vannucch MG, Traini C, Guasti D, Giulio DP, Faussone-Pellegrini MS (2014) Telocytes subtypes in human urinary bladder. J Cell Mol Med 18:2000–2008
Verdile N, Pasquariello R, Cardinaletti G, Tibaldi E, Brevini TAL, Gandolfi F (2021) TCs: active players in the rainbow trout (Oncorhynchus mykiss) intestinal stem-cell niche. Animals (basel) 12(1):74. https://doi.org/10.3390/ani12010074
Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O, Li M, Shen C, Hu A, Haydon RC, Kang R, Mok J, Lee MJ, Luu HL, Shi LL (2014) Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 1(1):87–105. https://doi.org/10.1016/j.gendis.2014.07.005
Winkler EA, Bell RD, Zlokovic BV (2010) Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol Neurodegener 25(5):32. https://doi.org/10.1186/1750-1326-5-32
Wei XJ, Chen TQ, Yang XJ (2022) TCs in fibrosis diseases: from current findings to future clinical perspectives. Cell Transplant. https://doi.org/10.1177/09636897221105252
Xu Y, Luan G, Li Z et al (2023) Tumour-derived exosomal lncRNA SNHG16 induces TCs to promote metastasis of hepatocellular carcinoma via the miR-942-3p/MMP9 axis. Cell Oncol 46:251–264. https://doi.org/10.1007/s13402-022-00746-w
Xu Y, Tian H, Cheng J, Liang S, Li T, Liu J (2019) Immunohistochemical biomarkers and distribution of TCs in ApoE-/- mice. Cell Biol Int 43(11):1286–1295. https://doi.org/10.1002/cbin.11128
Yang D, Yuan L, Chen S et al (2023) Morphological and histochemical identification of TCs in adult yak epididymis. Sci Rep 13:5295. https://doi.org/10.1038/s41598-023-32220-4
Yang J, Ii M, Kamei N, Alev C, Kwon SM, Kawamoto A, Akimaru H, Masuda H, Sawa Y, Asahara T (2011) CD34+ cells represent highly functional endothelial progenitor cells in murine bone marrow. PLoS ONE 6(5):e20219. https://doi.org/10.1371/journal.pone.0020219
Yang P, Zhu X, Wang L, Ahmed N, Huang Y, Chen H, Zhang Q, Ullah S, Liu T, Guo D, Brohi SA, Chen Q (2017) Cellular evidence of TCs as novel interstitial cells within the magnum of chicken oviduct. Cell Transplant 26(1):135–143. https://doi.org/10.3727/096368916X692942
Yang R, Tang Y, Chen X, Yang Y (2021) TCs-derived extracellular vesicles alleviate aortic valve calcification by carrying miR-30b. ESC Heart Fail 8(5):3935–3946. https://doi.org/10.1002/ehf2.13460. Epub 2021 Jun 24. PMID: 34165260; PMCID: PMC8497371
Yang XJ, Yang J, Liu Z, Yang G, Shen ZJ (2015) TCs damage in endometriosis-affected rat oviduct and potential impact on fertility. J Cell Mol Med 19(2):452–462. https://doi.org/10.1111/jcmm.12427
Zani BC, Sanches BDA, Maldarine JS, Biancardi MF, Santos FCA, Barquilha CN, Zucão MI, Baraldi CMB, Felisbino SL, Góes RM, Vilamaior PSL, Taboga SR (2018) TCs role during the postnatal development of the Mongolian gerbil jejunum. Exp Mol Pathol 105(1):130–138. https://doi.org/10.1016/j.yexmp.2018.07.003
Zhang H, Yu P, Zhong S, Ge T, Peng S, Guo X, Zhou Z (2016) TCs in pancreas of the Chinese giant salamander (Andrias davidianus). J Cell Mol Med 20(11):2215–2219. https://doi.org/10.1111/jcmm.12948
Zhang D, Song D, Shi L, Sun X, Zheng Y, Zeng Y, Wang X (2020) Mechanisms of interactions between lung-origin TCs and mesenchymal stem cells to treat experimental acute lung injury. Clin Transl Med 10(8):e231. https://doi.org/10.1002/ctm2.231
Zhao B, Chen S, Liu J, Yuan Z, Qi X, Qin J, Zheng X, Shen X, Yu Y, Qnin TJ, Chan JY, Cai D (2013) Cardiac TCs were decreased during myocardial infarction and their therapeutic effects for ischaemic heart in rat. J Cell Mol Med 17(1):123–133. https://doi.org/10.1111/j.1582-4934.2012.01655.x
Zhao J, Birjandi AA, Ahmed M, Redhead Y, Olea JV, Sharpe P (2022) TCs regulate macrophages in periodontal disease. Elife 4(11):e72128. https://doi.org/10.7554/eLife.72128
Zheng Y, Cretoiu D, Yan G, Cretoiu SM, Popescu LM, Fang H, Wang X (2014b) Protein profiling of human lung TCs and microvascular endothelial cells using iTRAQ quantitative proteomics. J Cell Mol Med 18(6):1035–1059. https://doi.org/10.1111/jcmm.12350
Zheng Y, Cretoiu D, Yan G, Cretoiu SM, Popescu LM, Wang X (2014a) Comparative proteomic analysis of human lung TCs with fibroblasts. J Cell Mol Med 18(4):568–589. https://doi.org/10.1111/jcmm.12290
Zheng Y, Zhang M, Qian M, Wang L, Cismasiu VB, Bai C, Popescu LM, Wang X (2013) Genetic comparison of mouse lung TCs with mesenchymal stem cells and fibroblasts. J Cell Mol Med 17(4):567–577. https://doi.org/10.1111/jcmm.12052.PMID:23621815;PMCID:PMC3822657
Zhu X, Wang Q, Pawlicki P, Wang Z, Pawlicka B, Meng X, Feng Y, Yang P (2022) TCs and their structural relationships with the sperm storage tube and surrounding cell types in the utero-vaginal junction of the chicken. Front Vet Sci 24(9):852407. https://doi.org/10.3389/fvets.2022.852407
Acknowledgements
We thank FAPESP and CNPq for the funding and the researchers of the School of Chemical Engineering, University of Birmingham, as well as of INFABIC lab at the State University of Campinas (UNICAMP).
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This work was supported by FAPESP (São Paulo Research Foundation) (contract number 2021/02303-7 (to HFC)) and CNPq (Brazilian National Council for Scientific and Technological Development) (contract numbers 465699/2014-6 (to HCF) and 104276/2023-1 (to BDAS)).
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Sanches, B.D.A., Teófilo, F.B.S., Brunet, M.Y. et al. Telocytes: current methods of research, challenges and future perspectives. Cell Tissue Res 396, 141–155 (2024). https://doi.org/10.1007/s00441-024-03888-5
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DOI: https://doi.org/10.1007/s00441-024-03888-5