Roles of pulmonary telocytes in airway epithelia to benefit experimental acute lung injury through production of telocyte-driven mediators and exosomes

Abstract

Background Telocytes (TCs) are experimentally evidenced as an alternative of cell therapies for organ tissue injury and repair. The aims of the present studies are to explore direct roles of TCs and the roles of TC-derived exosomes in support of experimental acute lung injury (ALI) in vivo or in vitro. Materials and methods The roles of TCs in experimental ALI were firstly estimated. Phosphoinositide 3-kinase (PI3K) p110δ and α/δ/β isoform inhibitors were used in study dynamic alterations of bio-behaviors, and in expression of functional factors of TCs per se and TC-co-cultured airway epithelial cells during the activation with lipopolysaccharide (LPS). TC-driven exosomes were furthermore characterized for intercellular communication by which activated or non-activated TCs interacted with epithelia. Results Our results showed that TCs mainly prevented from lung tissue edema and hemorrhage and decreased the levels of VEGF-A and MMP9 induced by LPS. Treatment with CAL101 (PI3K p110δ inhibitor) and LY294002 (PI3Kα/δ/β inhibitor) could inhibit TC movement and differentiation and increase the number of dead TCs. The expression of Mtor , Hif1α , Vegf-a , or Mmp9 mRNA increased in TCs challenged with LPS, while Mtor , Hif1α , and Vegf-a even more increased after adding CAL101 or Mtor after adding LY. The rate of epithelial cell proliferation was higher in co-culture of human bronchial epithelial (HBE) and TCs than that in HBE alone under conditions with or without LPS challenge or when cells were treated with LPS and CAL101 or LY294002. The levels of mTOR , HIF1α , or VEGF-A significantly increased in mono-cultured or co-cultured cells, challenged with LPS as compared with those with vehicle. LPS-pretreated TC-derived exosomes upregulated the expression of AKT, p-AKT, HIF1α, and VEGF-A protein of HBE. Conclusion The present study demonstrated that intraperitoneal administration of TCs ameliorated the severity of lung tissue edema accompanied by elevated expression of VEGF-A. TCs could nourish airway epithelial cells through nutrients produced from TCs, increasing epithelial cell proliferation, and differentiation as well as cell sensitivity to LPS challenge and PI3K p110δ and α/δ/β inhibitors, partially through exosomes released from TCs. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10565-021-09670-5.

Telocytes in the Female Reproductive System: Up-to-Date Knowledge, Challenges and Possible Clinical Applications

“…Without overstating, it can be said that TCs have been described in almost every organ one can think of. Except of the FRS, TCs have been discovered in the intestine [18], lungs [19], skeletal muscle [20], skin [21], ureter [22], heart [23], testes [24], prostate [25], eye [26], and even in remarkable locations such as a cow s teat [27]. TCs in the FRS are quite alike to TCs in other organs, but there are several morphological and functional characteristics that make them distinct.…”

Dynamic Involvement of Telocytes in Modulating Multiple Signaling Pathways in Cardiac Cytoarchitecture

“…Furthermore, the single-cell RNA-sequencing (scRNA-seq) scrutiny wild type (WT) using MESP1- KO murine embryos has disclosed that BMP4 could expressly mark the CM-committed population at E7.25 among MESP1 + mesodermal precursors [ 97 , 98 ]. Constitutive expression of TGFB is figured not only within both embryonic and adult CMs [ 88 ] but also within TCs [ 99 , 100 ]. Additionally, TGFB is conspicuously upregulated in models of experimental MI [ 86 ].…”

“…A growing body of evidence delineates that the PI3K/AKT signaling pathway plays a key role in a multitude of processes related to the incidence, advancement, and pathological generation of cardiac fibrogenesis via the regulation of cell survival, apoptosis and cardiac contractility, albeit activating the target genes [ 100 , 116 , 117 , 118 ]. Essentially, the triggering of PI3K by receptor tyrosine kinases determines phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to bring about phosphatidylinositol-3,4,5-triphosphate (PIP3) and activates the signaling pathway [ 119 ].…”

“…Likewise, another study indicated that PI3K deficiency safeguards against isoproterenol-induced HF and suggested that p110 gamma mediates pathological cardiac hypertrophy [ 129 ]. Notably, intraperitoneal administration of TCs improved the hardness of lung edemas associated with alterations in the mRNA expression of MTOR , HIF1A , VEGF , and MMP9 within TCs [ 100 ]. TCs could increase airway epithelia proliferation and differentiation through driven mediators and exosomes to compensate for experimental acute lung injury [ 100 ].…”

“…Notably, intraperitoneal administration of TCs improved the hardness of lung edemas associated with alterations in the mRNA expression of MTOR , HIF1A , VEGF , and MMP9 within TCs [ 100 ]. TCs could increase airway epithelia proliferation and differentiation through driven mediators and exosomes to compensate for experimental acute lung injury [ 100 ]. Further strategies to define the assignment of TCs in cardiomyogenesis, cardiac remodeling, and pathogenesis of heart diseases include extensive scrutiny of their gene expression profiles and cell lineage trajectory and will open an avenue in the disclosure of novel “smart” drugs to target CMs regeneration, based upon understanding context-specific molecular mechanisms.…”