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Review
. 2023 Dec;56(12):e13499.
doi: 10.1111/cpr.13499. Epub 2023 May 8.

mTOR signalling pathway in stem cell bioactivities and angiogenesis potential

Hamid Lotfimehr  1   2 , Narges Mardi  3 , Samaneh Narimani  2 , Hamid Tayefi Nasrabadi  1   2 , Mohammad Karimipour  2 , Emel Sokullu  4 , Reza Rahbarghazi  1   2
Affiliations
Review

mTOR signalling pathway in stem cell bioactivities and angiogenesis potential

Hamid Lotfimehr et al. Cell Prolif. 2023 Dec.

Abstract

The mammalian target of rapamycin (mTOR) is a protein kinase that responds to different stimuli such as stresses, starvation and hypoxic conditions. The modulation of this effector can lead to the alteration of cell dynamic growth, proliferation, basal metabolism and other bioactivities. Considering this fact, the mTOR pathway is believed to regulate the diverse functions in several cell lineages. Due to the pleiotropic effects of the mTOR, we here, hypothesize that this effector can also regulate the bioactivity of stem cells in response to external stimuli pathways under physiological and pathological conditions. As a correlation, we aimed to highlight the close relationship between the mTOR signalling axis and the regenerative potential of stem cells in a different milieu. The relevant publications were included in this study using electronic searches of the PubMed database from inception to February 2023. We noted that the mTOR signalling cascade can affect different stem cell bioactivities, especially angiogenesis under physiological and pathological conditions. Modulation of mTOR signalling pathways is thought of as an effective strategy to modulate the angiogenic properties of stem cells.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Mammalian target of rapamycin (mTOR) signalling pathway. The mTOR signalling pathway consists of two mTOR complexes, mTORC1 and mTORC2 with the ability to regulate different bioactivities inside the host cells. In upstream, several factors such as amino acids, Wnt, TNF‐α, IGF and insulin can affect the activity of mTOR. The mTORC1 complex regulates microtubule re‐organization, autophagy and lipolysis, lipid and protein synthesis while the mTORC2 complex is involved in cell survival and cytoskeletal re‐modelling.
FIGURE 2
FIGURE 2
Autophagy machinery following the mammalian target of rapamycin (mTOR) activity. mTOR inhibition can lead to the activation of ATG10, ATG13, ULK1 and FIP200 and formation of primary phagophores. This process is followed by elongation via the participation of the ATG7/ATG3/ATG4 complex and the conversion of LC3‐I to LC3‐II, leading to the formation of autophagosomes. After that, autophagosomes are fused with lysosomes to form autophagolysosomes. In the latter steps, the autophagic cargo is released to the outside of cells or recycled.
FIGURE 3
FIGURE 3
The role of mammalian target of rapamycin (mTOR) in cutaneous tissue angiogenesis (A–H). In vivo angiogenesis was induced using an active form of Cathelicidin namely LL37. Immunofluorescence staining of CD31 and pS6 was performed in rosacea patients and compared to the normal samples (HS) (A, B). Immunostaining of CD31 and pS6 in mice cutaneous samples after treatment with LL37 and rapamycin (C, D; White arrows: CD31+ cells). Semi‐quantitative measuring of CD31 vessels in LL37‐treated rosacea‐like mice after treatment with rapamycin (E, F). Semi‐quantitative measuring of CD31+ vessels in control and TSC2+/− knockdown mice after treatment with LL37 (G, H). Real‐time PCR analysis of VEGF in normal and TSC2+/− knockdown mice treated with LL37. Scale bar: 50 μm. Student's t‐test (B). One‐way ANOVA with Bonferroni's post‐hoc test (D, F, H and I). *p < 0.05; **p < 0.01 (Copyright 2021, Frontiers in Cell and Developmental Biology).
FIGURE 4
FIGURE 4
Pro‐angiogenesis properties of rat bone marrow mesenchymal stem cells (MSCs) in cardiac ischemia/reperfusion model. GFP‐expressing MSCs were pre‐treated with rapamycin and transplanted into the affected sites in cardiac tissue. Immunofluorescence imaging revealed that GFP+ MSCs can express CD31 (white arrows) and align in the vascular lumen, indicating the stimulatory role of mammalian target of rapamycin inhibition on endothelial lineage differentiation of MSCs. Scale bar = 100 μm. *p < 0.01 related to control; # p < 0.01 related to MSC group (n = 6) (Copyright 2021, Pharmaceuticals).
FIGURE 5
FIGURE 5
Pro‐angiogenesis properties of rat bone marrow mesenchymal stem cells (MSCs) in cardiac ischemia/reperfusion model. GFP‐expressing MSCs were pre‐treated with rapamycin and transplanted into the affected sites in cardiac tissue. Immunofluorescence imaging revealed that GFP+ MSCs can express CD31 (white arrows) and align in the vascular lumen, indicating the stimulatory role of mTOR inhibition on endothelial lineage differentiation of MSCs. Scale bar = 100 μm. *p < 0.01 related to control; # p < 0.01 related to MSC group (n = 6) (Copyright 2020, Stem Cell Reviews and Reports).
FIGURE 6
FIGURE 6
Evaluation of angiogenesis and apoptosis rate in ovarian tissue of rats with premature ovarian failure (POF) (A–G). Immunofluorescence imaging revealed that the number of TUNEL+ cells was reduced in the POF rats that received miR‐126‐3p‐bearing Exo (A). Immunohistochemistry staining indicated increased PCNA cell number in ovarian follicles, indicating the number of proliferating cells (B). In line with these changes, the number of CD31+ cells was increased in the POF rats that received 126‐3p‐bearing Exo (C). Western blotting indicated the suppression of apoptosis‐related Bax, Caspase 3, and induction of anti‐apoptotic factor Bcl‐2 (D, E). 126‐3p‐bearing Exo increased protein levels of FGF, VEGF and IGF‐1 in the ovarian tissue (n = 10). One‐way ANOVA analysis. hucMSC, human umbilical cord MSCs derived exosomes; NC, negative control; PCNA, Proliferating cell nuclear antigen. *p < 0.05 (Copyright 2022, Stem Cell Research & Therapy).
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