scholarly journals Pro-Angiogenic and Osteogenic Effects of Adipose Tissue-Derived Pericytes Synergistically Enhanced by Nel-like Protein-1

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2244
Author(s):  
Hyun-Ju An ◽  
Kyung Rae Ko ◽  
Minjung Baek ◽  
Yoonhui Jeong ◽  
Hyeon Hae Lee ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Migration ◽  
Mouse Model ◽  
Bone Formation ◽  
Synergistic Effects ◽  
Tube Formation ◽  
Therapeutic Effects ◽  
Efficacy Evaluation ◽  
Vessel Formation ◽  
Quantitative Analyses

An important objective of vascularized tissue regeneration is to develop agents for osteonecrosis. We aimed to identify the pro-angiogenic and osteogenic efficacy of adipose tissue-derived (AD) pericytes combined with Nel-like protein-1 (NELL-1) to investigate the therapeutic effects on osteonecrosis. Tube formation and cell migration were assessed to determine the pro-angiogenic efficacy. Vessel formation was evaluated in vivo using the chorioallantoic membrane assay. A mouse model with a 2.5 mm necrotic bone fragment in the femoral shaft was used as a substitute for osteonecrosis in humans. Bone formation was assessed radiographically (plain radiographs, three-dimensional images, and quantitative analyses), and histomorphometric analyses were performed. To identify factors related to the effects of NELL-1, analysis using microarrays, qRT-PCR, and Western blotting was performed. The results for pro-angiogenic efficacy evaluation identified synergistic effects of pericytes and NELL-1 on tube formation, cell migration, and vessel formation. For osteogenic efficacy analysis, the mouse model for osteonecrosis was treated in combination with pericytes and NELL-1, and the results showed maximum bone formation using radiographic images and quantitative analyses, compared with other treatment groups and showed robust bone and vessel formation using histomorphometric analysis. We identified an association between FGF2 and the effects of NELL-1 using array-based analysis. Thus, combinatorial therapy using AD pericytes and NELL-1 may have potential as a novel treatment for osteonecrosis.

scholarly journals Pro-angiogenic and osteogenic effects of adipose tissue-derived pericytes synergistically enhanced by Nel-like protein-1

2021 ◽  
Author(s):  
Hyun-Ju An ◽  
Kyung Rae Ko ◽  
Minjung Baek ◽  
Yoonhui Chung ◽  
Hyunhae Lee ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Migration ◽  
Bone Formation ◽  
Synergistic Effects ◽  
Tube Formation ◽  
Pcr Analysis ◽  
Therapeutic Effects ◽  
Vessel Formation ◽  
Quantitative Analyses

Abstract Background One of important objectives of regeneration of vascularized tissues is to develop agents for osteonecrosis. We aimed to determine pro-angiogenic and osteogenic efficacies of adipose tissue-derived (AD) pericytes combined with Nel-like protein-1 (NELL-1) to investigate their therapeutic effects for osteonecrosis. Methods The experimental groups were configured to evaluate additional effects of NELL-1 on pericytes (i.e., Control, the group treated with only NELL-1, the group treated with only pericytes, and the group treated with pericytes and NELL-1). Tube formation and cell migration were assessed to determine pro-angiogenic efficacy. In vivo vessel formation was evaluated using the chorioallantoic membrane assay. A mouse model with a 2.5-mm necrotic bone fragment at the femoral shaft was used as a substitute for osteonecrosis in humans. Bone formation was assessed radiographically (plain radiographs, three-dimensional images, and quantitative analyses). Histomorphometric analyses were also performed. To identify factors related to additional effects of NELL-1, microarray, qRT-PCR analysis, and western blot were performed. Results The results for pro-angiogenic efficacy indicated there were synergistic effects of pericytes and NELL-1 on tube formation, cell migration, and vessel formation. For the results for osteogenic efficacy, the mouse models of osteonecrosis treated with pericytes and NELL-1 revealed the greatest bone formation in radiographic images and quantitative analyses, compared with other settings. The corresponding models treated with pericytes and NELL-1 revealed robust bone and vessel formation in the histomorphometric analyses. Using additional arrays, we found an association of FGF2 between the effects of NELL-1. Conclusion Combinational therapy using AD pericytes and NELL-1 has potential as a novel treatment for osteonecrosis.

scholarly journals Characterization of Glyceollins as Novel Aryl Hydrocarbon Receptor Ligands and Their Role in Cell Migration

2020 ◽  
Vol 21 (4) ◽  
pp. 1368 ◽  
Author(s):  
Thu Ha Pham ◽  
Sylvain Lecomte ◽  
Remy Le Guevel ◽  
Aurélie Lardenois ◽  
Bertrand Evrard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Aryl Hydrocarbon Receptor ◽  
Synergistic Effects ◽  
Binding Pocket ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Computational Docking ◽  
Aryl Hydrocarbon ◽  
Glyceollin I

Recent studies strongly support the use of the aryl hydrocarbon receptor (AhR) as a therapeutic target in breast cancer. Glyceollins, a group of soybean phytoalexins, are known to exert therapeutic effects in chronic human diseases and also in cancer. To investigate the interaction between glyceollin I (GI), glyceollin II (GII) and AhR, a computational docking analysis, luciferase assays, immunofluorescence and transcriptome analyses were performed with different cancer cell lines. The docking experiments predicted that GI and GII can enter into the AhR binding pocket, but their interactions with the amino acids of the binding site differ, in part, from those interacting with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Both GI and GII were able to weakly and partially activate AhR, with GII being more potent. The results from the transcriptome assays showed that approximately 10% of the genes regulated by TCDD were also modified by both GI and GII, which could have either antagonistic or synergistic effects upon TCDD activation. In addition, we report here, on the basis of phenotype, that GI and GII inhibit the migration of triple-negative (ER-, PgR-, HER2NEU-) MDA-MB-231 breast cancer cells, and that they inhibit the expression of genes which code for important regulators of cell migration and invasion in cancer tissues. In conclusion, GI and GII are AhR ligands that should be further investigated to determine their usefulness in cancer treatments.

scholarly journals Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells on Concanavalin A-Induced Acute Liver Injury in Mice

Cell Medicine ◽  
2017 ◽  
Vol 9 (1-2) ◽  
pp. 21-33 ◽  
Author(s):  
Yasuma Yoshizumi ◽  
Hiroshi Yukawa ◽  
Ryoji Iwaki ◽  
Sanae Fujinaka ◽  
Ayano Kanou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Mouse Model ◽  
Cell Therapy ◽  
Concanavalin A ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Immunomodulatory Effects

Cell therapy with adipose tissue-derived stem cells (ASCs) is expected to be a candidate for the treatment of fulminant hepatic failure (FHF), which is caused by excessive immune responses. In order to evaluate the therapeutic effects of ASCs on FHF, the in vitro and in vivo immunomodulatory effects of ASCs were examined in detail in the mouse model. The in vitro effects of ASCs were examined by assessing their influence on the proliferation of lymphomononuclear cells (LMCs) stimulated with three kinds of mitogens: phorbol 12-myristate 13-acetate (PMA) plus ionomycin, concanavalin A (ConA), and lipopolysaccharide (LPS). The proliferation of LMCs was efficiently suppressed in a dose-dependent manner by ASCs in the cases of PMA plus ionomycin stimulation and ConA stimulation, but not in the case of LPS stimulation. The in vivo effects of transplanted ASCs were examined in the murine FHF model induced by ConA administration. The ALT levels and histological inflammatory changes in the ConA-administered mice were apparently relieved by the transplantation of ASCs. The analysis of mRNA expression patterns in the livers indicated that the expressions of the cytokines such as Il-6, Il-10, Ifn-γ, and Tnf-α, and the cell surface markers such as Cd3γ, Cd4, Cd8α, Cd11b, and Cd11c were downregulated in the ASC-transplanted mice. The immunomodulatory and therapeutic effects of ASCs were confirmed in the mouse model both in vitro and in vivo. These suggest that the cell therapy with ASCs is beneficial for the treatment of FHF.

Abstract 17239: miRNAs Secreted by Exosomes Derived From Adipose Tissue Mesenchymal Stem Cells Overexpressing GATA-4 Increase Endothelial Cell Survival and Promote Angiogenesis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jie Xu ◽  
Jiapeng Wang ◽  
Min Liu ◽  
Yigang Wang ◽  
Muhammad Ashraf ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Structure Formation ◽  
Negative Control ◽  
Cell Behavior ◽  
Therapeutic Effects ◽  
Cell Based Therapy

Exosomes (EXO) secreted from stem cells play a critical role in cell based therapy and appear to have greater salutary therapeutic effects than whole cells. Our previous study showed that EXO produced by GATA-4-overexpressing mesenchymal stem cells (MSCs) significantly promoted angiogenesis and protected cardiomyocytes resulting in improved ischemic myocardial function. In the present studies, we compared the miR expression pattern and determined whether Exo GATA-4 delivered miRs particularly promoted angiogenesis. Methods and Results: EXO were collected from conditioned medium of adipose tissue derived MSCs that were transfected with GATA-4 (Exo GATA-4 ) or with vector-empty (Exo null ) using ultracentrifugation ( Fig A ). Functional analysis showed that Exo GATA-4 significantly increased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) compared to Exo null . MicroRNA-seq data showed that 7 of the 230 miRs found in EXO, were significantly upregulated in Exo GATA-4 ( Fig B ). To determine the effect of upregulated miRs on Exo GATA-4 mediated angiogenesis, miR-155 and miR-6240 mimic, inhibitor, and negative control were directly transferred into HUVECs. After 48 hours, HUVECs were harvested for measuring endothelial cell behavior. Transfection of miR-6240-mimic significantly increased HUVECs proliferation, tolerance against H 2 O 2 induced injury ( Fig C ), tube-like structure formation ( Fig D ) and cell migration ( Fig E ) compared to those transfected with negative control. Concurrently, no significant differences were found in proliferation, survival, and tube-like structure formation among the cells transfected with miR-155-mimic and negative control, although miR-155-mimic significantly increased cell migration. Conclusion: The upregulated miRs in Exo GATA-4 may variably regulate endothelial cell behavior and the role of various miRs needs to be investigated individually.

scholarly journals M1 Macrophage-Derived Nanovesicles Repolarize M2 Macrophages for Inhibiting the Development of Endometriosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiuju Li ◽  
Ming Yuan ◽  
Xue Jiao ◽  
Yufei Huang ◽  
Jing Li ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tube Formation ◽  
Reproductive Age ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Social Burden ◽  
M1 Macrophage ◽  
And Migration ◽  
Gynecological Disorder

BackgroundEndometriosis is a common nonmalignant gynecological disorder that affects 10–15% women of reproductive age and causes several symptoms that result in decreased quality of life and a huge social burden. In recent decades, extracellular vesicles (EVs) have gained attention as a potential therapeutic tool; however, the therapeutic effects of EVs against endometriosis have not been reported. Accordingly, in this study, we investigated the feasibility of nanovesicles (NVs) derived from M1 macrophages (M1NVs) in treating endometriosis.MethodsM1NVs were prepared by serial extrusion. Co-culture assays were performed to investigate changes in tube formation and migration/invasion of eutopic endometrial stroma cells (ESCs) obtained from patients with endometriosis (EM-ESCs). A mouse model of endometriosis was established, and mice were treated with phosphate-buffered saline, M0NVs, or M1NVs to evaluate the efficacy and safety of M1NV for treating endometriosis.ResultsM1NVs directly or indirectly inhibited the migration and invasion of EM-ESCs and reduced tube formation. In the mouse model, M1NVs suppressed the development of endometriosis through reprogramming of M2 macrophages, without causing damage to the organs.ConclusionsM1NVs inhibit the development of endometriosis directly, or through repolarizing macrophages from M2 to M1 phenotype. Hence, administration of M1NVs may represent a novel method for the treatment of endometriosis.

Therapeutic effects of lisinopril and empagliflozin in a mouse model of hypertension-accelerated diabetic kidney disease

2021 ◽  
Author(s):  
Mette Viberg Østergaard ◽  
Thomas Secher ◽  
Michael Christensen ◽  
Casper Gravesen Salinas ◽  
Urmas Roostalu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Diabetic Kidney Disease ◽  
Synergistic Effects ◽  
Standard Of Care ◽  
Therapeutic Interventions ◽  
Therapeutic Effects ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Control Disease

Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a mouse model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice. Five weeks after single AAV administration and four weeks after UNx, female db/db UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg) or combination treatment for 12 weeks (n=17 per group). Untreated db/+ mice (n=8) and vehicle-dosed db/db UNx-LacZAAV mice (n=17) served as controls. Endpoints included plasma, urine and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume was evaluated by whole-kidney 3D imaging analysis. db/db UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury and inflammation. While empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal outcomes. In conclusion, the db/db UNx-ReninAAV mouse demonstrates good clinical translatability with respect to the physiological and histological hallmarks of progressive DKD. Efficacy of standard of care to control hypertension and hyperglycemia provides proof-of-concept for testing novel drug therapies in the model.

scholarly journals Synergistic effects of exosomal crocin or curcumin compounds and HPV L1-E7 polypeptide vaccine construct on tumor eradication in C57BL/6 mouse model

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258599
Author(s):  
Elnaz Abbasifarid ◽  
Azam Bolhassani ◽  
Shiva Irani ◽  
Fattah Sotoodehnejadnematalahi
Keyword(s):  
Cervical Cancer ◽  
Mouse Model ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Low Cost ◽  
Hpv Infection ◽  
Therapeutic Effects ◽  
T Cell Immune Responses

Cervical cancer is the most common malignant tumor in females worldwide. Human papillomavirus (HPV) infection is associated with the occurrence of cervical cancer. Thus, developing an effective and low-cost vaccine against HPV infection, especially in developing countries is an important issue. In this study, a novel HPV L1-E7 fusion multiepitope construct designed by immunoinformatics tools was expressed in bacterial system. HEK-293T cells-derived exosomes were generated and characterized to use as a carrier for crocin and curcumin compounds. The exosomes loaded with crocin and curcumin compounds as a chemotherapeutic agent (ExoCrocin and ExoCurcumin) were used along with the L1-E7 polypeptide for evaluation of immunological and anti-tumor effects in C57BL/6 mouse model. In vitro studies showed that ExoCrocin and ExoCurcumin were not cytotoxic at a certain dose, and they could enter tumor cells. In vivo studies indicated that combination of the L1-E7 polypeptide with ExoCrocin or ExoCurcumin could produce a significant level of immunity directed toward Th1 response and CTL activity. These regimens showed the protective and therapeutic effects against tumor cells (the percentage of tumor-free mice: ~100%). In addition, both ExoCrocin and ExoCurcumin represented similar immunological and anti-tumor effects. Generally, the use of exosomal crocin or curcumin forms along with the L1-E7 polypeptide could significantly induce T-cell immune responses and eradicate tumor cells.

scholarly journals Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Binghua Xue ◽  
Xiuxiao Xiao ◽  
Tingting Yu ◽  
Xinhua Xiao ◽  
Jing Xie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Blood Glucose ◽  
Mouse Model ◽  
Synergistic Effects ◽  
Physiological Saline ◽  
Therapeutic Effects ◽  
Stem Cell Treatment ◽  
Positive Controls

Abstract Objective The purpose of this study was to investigate the therapeutic effects of genetically modified mesenchymal stem cells (MSCs) in the treatment of type 2 diabetes mellitus (T2DM) in order to identify a new method for treating diabetes that differs from traditional medicine and to provide a new means by which to fundamentally improve or treat diabetes. Methods MSCs derived from adipose tissue were modified to overexpress FGF21 and GLP1, which was achieved through lentiviral particle transduction. The cells were transplanted into BKS.Cg-Dock7m+/+Leprdb/Nju mice (T2DM mouse model). Injections of physiological saline (0.1 mL) and liraglutide (0.5 mg/kg) were used as negative and positive controls, respectively. ELISA or Western blotting was used for protein analysis, and quantitative real-time PCR was used for gene expression analysis. Results Genetic modification had no effects on the morphology, differentiation ability, or immunophenotype of MSCs. Moreover, MSC-FGF21+GLP1 cells exhibited significantly increased secretion of FGF21 and GLP1. In the T2DM mouse model, the transplantation of MSC-FGF21+GLP1 cells ameliorated the changes in blood glucose and weight, promoted the secretion of insulin, enhanced the recovery of liver structures, and improved the profiles of lipids. Moreover, FGF21 and GLP1 exerted synergistic effects in the regulation of glucolipid metabolism by controlling the expression of insulin, srebp1, and srebp2. Conclusion Stem cell treatment based on MSCs modified to overexpress the FGF21 and GLP1 genes is an effective approach for the treatment of T2DM.

scholarly journals Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

2021 ◽  
Author(s):  
Danielle A. Simmons ◽  
Brian D. Mills ◽  
Robert R. Butler III ◽  
Jason Kuan ◽  
Tyne L. M. McHugh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Disease Onset ◽  
Therapeutic Effects ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

Sign in / Sign up

Export Citation Format

Share Document