Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue

Mihai, M.; Popa, Mónica; Suica, Viorel I.; Antohe, Felicia; Jackson, Edwin K.; Simionescu, Maya; Dubey, Raghvendra K.

doi:10.1016/j.yjmcc.2019.06.007

Cited by 11 publications

(21 citation statements)

References 24 publications

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“…Indeed, MSCs and its secreted angiogenic mediators have been shown to induce angiogenesis and thereby enhancing tissue repair and functional outcomes in a variety of pathologies associated with insufficient angiogenesis. [51][52][53] Moreover, VEGF functions not only as one of the most important regulators of vascular development and angiogenesis, it also plays critical roles in skeletal development, 54 which is consistent with our qPCR results in vivo and vitro. Although several other angiogenic factors in the GIT1 KO group also showed different degrees of decline, the change in VEGF mRNA was most remarkable.…”

Section: Discussionsupporting

confidence: 89%

GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis

Tang

Zhou

et al. 2019

Cell Proliferation

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Objectives Osteogenesis is coupled with angiogenesis during bone remodelling. G‐protein‐coupled receptor (GPCR) kinase 2‐interacting protein‐1 (GIT1) is an important protein that participates in fracture healing by regulating angiogenesis. This study investigated whether GIT1 could affect bone mesenchymal stem cells (BMSCs) to secrete angiogenic factors to enhance fracture healing by promoting angiogenesis and its possible mechanism. Materials and methods The angiogenesis of mice post‐fracture was detected by micro‐CT and immunofluorescence. Subsequently, vascular endothelial growth factor (VEGF) level in mouse and human BMSCs (hBMSCs) under TNF‐α stimulation was detected. The hBMSCs were transfected with GIT1 shRNAs to further explore the relationship between GIT1 and VEGF and angiogenesis in vitro. Furthermore, based on previous research on GIT1, possible signal pathways were investigated. Results GIT1 knockout mice exhibited impaired angiogenesis and delayed fracture healing. And GIT1 deficiency remarkably reduced the expression of VEGF mRNA in BMSCs, which affected the proliferation and migration of human umbilical vein endothelial cells. GIT1 knockdown inhibited the activation of Notch and NF‐κB signals by decreasing nuclear transportation of NICD and P65/P50, respectively. Overexpression of the canonical NF‐κB subunits P65 and P50 markedly increased NICD‐dependent activation of recombination signal‐binding protein‐jκ reporter. Finally, GIT1 enhanced the affinity of NF‐κB essential modulator (NEMO) for K63‐linked ubiquitin chains via interaction with NEMO coiled‐coil 2 domains. Conclusion These data revealed a positive role for GIT1 by modulating the Notch/NF‐κB signals which promoting paracrine of BMSCs to enhance angiogenesis and fracture healing.

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Section: Discussionsupporting

confidence: 89%

GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis

Tang

Zhou

et al. 2019

Cell Proliferation

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“…The MSCs used express both estrogen receptors α and β and was confirmed by us previously using Western blotting [15] and shown in Figure S1A.…”

Section: Cell Culture-isolation and Characterization Of Wj-derived Mesenchymal Stem Cellssupporting

confidence: 66%

“…(5) pathways for growth signaling (MAPK/JAK-STAT/PI3K), cell adhesion, and energy metabolism; (6) transcriptional factors [15]; and (7) circulating progenitor endothelial cells known to induce angiogenesis [25].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Estrogen-Mediated Enhancement of Mesenchymal Stem Cell-Induced Angiogenesis In Vivo

Mihai

Popa

Suica

et al. 2021

Cells

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Therapeutic use of mesenchymal stem cells (MSCs) for tissue repair has great potential. MSCs from multiple sources, including those derived from human umbilical matrix, namely Wharton’s jelly, may serve as a resource for obtaining MSCs. However, low in vivo engraftment efficacy of MSCs remains a challenging limitation. To improve clinical outcomes using MSCs, an in-depth understanding of the mechanisms and factors involved in successful engraftment is required. We recently demonstrated that 17β-estradiol (E2) improves MSCs in vitro proliferation, directed migration and engraftment in murine heart slices. Here, using a proteomics approach, we investigated the angiogenic potential of MSCs in vivo and the modulatory actions of E2 on mechanisms involved in tissue repair. Specifically, using a Matrigel® plug assay, we evaluated the effects of E2 on MSCs-induced angiogenesis in ovariectomized (OVX) mice. Moreover, using proteomics we investigated the potential pro-repair processes, pathways, and co-mechanisms possibly modified by the treatment of MSCs with E2. Using RT-qPCR, we evaluated mRNA expression of pro-angiogenic molecules, including endoglin, Tie-2, ANG, and VEGF. Hemoglobin levels, a marker for blood vessel formation, were increased in plugs treated with E2 + MSCs, suggesting increased capillary formation. This conclusion was confirmed by the histological analysis of capillary numbers in the Matrigel® plugs treated with E2 + MSC. The LC-MS screening of proteins obtained from the excised Matrigel® plugs revealed 71 proteins that were significantly altered following E2 exposure, 57 up-regulated proteins and 14 down-regulated proteins. A major result was the association of over 100 microRNA molecules (miRNAs) involved in cellular communication, vesicle transport, and metabolic and energy processes, and the high percentage of approximately 25% of genes involved in unknown biological processes. Together, these data provide evidence for increased angiogenesis by MSCs treated with the sex hormone E2. In conclusion, E2 treatment may increase the engraftment and repair potential of MSCs into tissue, and may promote MSC-induced angiogenesis after tissue injury.

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“…Angiogenin has been well characterized as a angiogenic factor in tumor growth and is induced by other angiogenic factors including vascular endothelial growth factor and epidermal growth factor (21). Angiogenin was also detected in the secretomes of human MSCs and has been found to be important for enhancing the regenerative potential of MSCs in various diseases, as well as in repairing vascular injury (22–25). Moreover, several lines of evidence suggest that angiogenin is involved in the innate immune system and is associated with inflammatory activation.…”

Section: Discussionmentioning

confidence: 99%

Perivascular Stem Cells Suppress Inflammasome Activation during Inflammatory Responses in Macrophages

Kim

et al. 2019

IJSC

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Background and ObjectivesPerivascular stem cells (PVCs) have been identified as precursors of mesenchymal stem cells (MSCs) that offer promising prospects for application in the development of cellular therapies. Although PVCs have been demonstrated to have greater therapeutic potential compared to bone marrow and adipose tissue-derived MSCs in various diseases, the regulatory role of PVCs on inflammasome activation during macrophage-mediated inflammatory responses has not been investigated.Methods and ResultsIn this study, we found that the PVC secretome effectively alleviates secretion of both caspase-1 and interleukin-1β in lipopolysaccharide-primed and activated human and murine macrophages by blocking inflammasome activation and attenuating the production of mitochondrial reactive oxygen species (ROS). We further showed that the PVC secretome significantly reduces inflammatory responses and endoplasmic reticulum stress in peritoneal macrophages in a mouse model of monosodium urate-induced peritonitis. A cytokine antibody array analysis revealed that the PVC secretome contains high levels of serpin E1 and angiogenin, which may be responsible for the inhibitory effects on mitochondrial ROS generation as well as on inflammasome activation.ConclusionsOur results suggest that PVCs may be therapeutically useful for the treatment of macrophage- and inflammation-mediated diseases by paracrine action via the secretion of various biological factors.

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Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue

Cited by 11 publications

References 24 publications

GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis

GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis

Proteomic Analysis of Estrogen-Mediated Enhancement of Mesenchymal Stem Cell-Induced Angiogenesis In Vivo

Perivascular Stem Cells Suppress Inflammasome Activation during Inflammatory Responses in Macrophages

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