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Kwan KYC, Li K, Wang YY, Tse WY, Tong CY, Zhang X, Wang DM, Ker DFE. The Characterization of Serum-Free Media on Human Mesenchymal Stem Cell Fibrochondrogenesis. Bioengineering (Basel) 2025; 12:546. [PMID: 40428164 PMCID: PMC12109459 DOI: 10.3390/bioengineering12050546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 05/03/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Developing fibrochondrogenic serum-free media is important for regenerating diseased and injured fibrocartilage but no defined protocols exist. Towards this goal, we characterized the effect of four candidate fibrochondrogenic serum-free media containing transforming growth factor beta-3 (TGF-β3), insulin-like growth factor-1 (IGF-1), and fibroblast growth factor-2 (FGF-2) with high/low glucose and with/without dexamethasone on human mesenchymal stem cells (hMSCs) via proliferation and differentiation assays. In Ki67 proliferation assays, serum-free media containing low glucose and dexamethasone exhibited the highest growth. In gene expression assays, serum-free media containing low glucose and commercially available chondrogenic media (COM) induced high fibrochondrogenic transcription factor expression (scleraxis/SCX and SRY-Box Transcription Factor 9/SOX9) and extracellular matrix (ECM) protein levels (aggrecan/ACAN, collagen type I/COL1A1, and collagen type II/COL2A1), respectively. In immunofluorescence staining, serum-free media containing high glucose and COM induced high fibrochondrogenic transcription factor (SCX and SOX9) and ECM protein (COL1A1, COL2A1, and collagen type X/COL10A1) levels, respectively. In cytochemical staining, COM and serum-free media containing dexamethasone showed a high collagen content whereas serum-free media containing high glucose and dexamethasone exhibited high glycosaminoglycan (GAG) levels. Altogether, defined serum-free media containing high glucose exhibited the highest fibrochondrogenic potential. In summary, this work studied conditions conducive for fibrochondrogenesis, which may be further optimized for potential applications in fibrocartilage tissue engineering.
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Affiliation(s)
- Ka Yu Carissa Kwan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Ke Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Yu Yang Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Wai Yi Tse
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Chung Yan Tong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Xu Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, Hong Kong SAR, China
| | - Dan Michelle Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; (K.Y.C.K.); (K.L.); (Y.Y.W.); (W.Y.T.); (C.Y.T.); (X.Z.); (D.M.W.)
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, Hong Kong SAR, China
- Ministry of Education Key Laboratory for Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Dai Fei Elmer Ker
- Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
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Wang T, Chen J, Qu B, Zhou D, Hong Z. Scutellarin Alleviates Bone Marrow Mesenchymal Stromal Cellular Senescence via the Ezh2-Nrf2 Signalling Axis in Diabetes-Induced Bone Loss. Cell Prolif 2025; 58:e13790. [PMID: 39668494 PMCID: PMC11969241 DOI: 10.1111/cpr.13790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/08/2024] [Accepted: 11/27/2024] [Indexed: 12/14/2024] Open
Abstract
Currently, there is no specific treatment for diabetes-induced osteoporosis (DOP). Our study identified diabetes-induced cellular senescence, marked by elevated activity of senescence-associated β-galactosidase. Targeting senescent cells holds promise for osteoporosis treatment. We demonstrated that scutellarin (SCU) effectively mitigated bone loss in DOP mice, and co-treatment with SCU significantly reduced diabetes-induced senescence in LepR+MSCs. Furthermore, our research highlighted the role of Nrf2 in SCU's anti-senescence effects on bone. The deletion of Nrf2 impaired SCU's ability to alleviate DOP. Mechanistically, SCU enhances Ezh2 expression and increases H3K27me3 activity at the Keap1 promoter region, leading to Keap1 repression and enhanced Nrf2-ARE signalling. Additionally, SCU notably inhibited cellular senescence and diabetes-related osteoporosis, these effects were significantly reduced in Ezh2LepRcre conditional knockout models. These findings suggest that the Ezh2-Nrf2 signalling axis is crucial for mediating SCU's beneficial effects in this context. Overall, our discoveries provide insights into the mechanisms underlying DOP and propose a potential preventive strategy for this condition.
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Affiliation(s)
- Tiantian Wang
- Department of NeurologyInstitute of Neurology and Disease, West China Hospital of Sichuan UniversityChengduChina
- Institute of Brain Science and Brain‐Inspired Technology of West China Hospital, Sichuan UniversityChengduChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduChina
| | - Jiehao Chen
- Animal Laboratory Center, West China Hospital, Sichuan UniversityChengduChina
| | - Bo Qu
- Department of OrthopedicsThe First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Dong Zhou
- Department of NeurologyInstitute of Neurology and Disease, West China Hospital of Sichuan UniversityChengduChina
- Institute of Brain Science and Brain‐Inspired Technology of West China Hospital, Sichuan UniversityChengduChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduChina
| | - Zhen Hong
- Department of NeurologyInstitute of Neurology and Disease, West China Hospital of Sichuan UniversityChengduChina
- Institute of Brain Science and Brain‐Inspired Technology of West China Hospital, Sichuan UniversityChengduChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduChina
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Kim JE, Lee JW, Cha GD, Yoon JK. The Potential of Mesenchymal Stem Cell-Derived Exosomes to Treat Diabetes Mellitus. Biomimetics (Basel) 2025; 10:49. [PMID: 39851765 PMCID: PMC11760843 DOI: 10.3390/biomimetics10010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 12/27/2024] [Accepted: 12/31/2024] [Indexed: 01/26/2025] Open
Abstract
Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.
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Affiliation(s)
| | | | | | - Jeong-Kee Yoon
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si 17546, Gyeonggi-do, Republic of Korea (G.D.C.)
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Xing L, Mondesir R, Glasstetter LM, Zhu XY, Lu B, Al Saeedi M, Sohi GK, Eirin A, Lerman LO. The Impact of Obesity on Autophagy in Human Adipose-Derived Mesenchymal Stromal Cells. Cell Transplant 2025; 34:9636897251323339. [PMID: 40116436 PMCID: PMC11930488 DOI: 10.1177/09636897251323339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/14/2025] [Accepted: 02/06/2025] [Indexed: 03/23/2025] Open
Abstract
Mesenchymal stromal cells (MSCs) possess therapeutic properties, which can be blunted by obesity. Autophagy, a cellular recycling process, is essential for MSC function. We investigated the mechanisms by which obesity affects the properties of MSCs, with a focus on autophagy. Adipose tissue was obtained from kidney donors [body mass index (BMI) <30 kg/m2, non-obese] or individuals undergoing weight loss surgery (BMI ≥30 kg/m2, obese) for MSC harvesting (n = 11 each); samples were randomized to sequencing (seq; n = 5 each) or functional studies (n = 6 each). MSCs were sequenced to determine their epigenetic (5-hydroxymethylcytosine) and transcriptomic profiles across autophagy-related genes using hydroxymethylated DNA immunoprecipitation sequencing and mRNA-seq, respectively. Genes with shared trends in both datasets underwent Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) validation. During functional studies, 2-h starvation was used to induce autophagy in vitro, enabling detection of changes in the protein expression of microtubule-associated protein 1A/1B-light chain-3 and in autophagic flux. Obesity amplified a starvation-induced reduction in autophagic flux in MSCs while promoting earlier generation of new autophagosomes during autophagy initiation. Integrated analysis of the two sequencing datasets revealed 124 differentially hydroxymethylated genes and 30 differentially expressed mRNAs. Among six overlapping autophagy-related genes, three exhibited same-direction trends. Of these, STX12 and SLC25A4 may be implicated in the impact of obesity on autophagic changes in MSCs. Therefore, human obesity may alter autophagy in adipose tissue-derived MSC, and thereby their metabolism and function.
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Affiliation(s)
- Li Xing
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
- Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Ronscardy Mondesir
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | | | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Bo Lu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mina Al Saeedi
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | | | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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Zou YC, Gao K, Cao BT, He XL, Zheng W, Wang XF, Li YF, Li F, Wang HJ. Syringin protects high glucose-induced BMSC injury, cell senescence, and osteoporosis by inhibiting JAK2/STAT3 signaling. J Appl Biomed 2024; 22:197-207. [PMID: 40033807 DOI: 10.32725/jab.2024.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 10/16/2024] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Acanthopanax senticosus (Rupr. et Maxim.) is commonly used in Traditional Chinese Medicine. Syringin is a major ingredient of phenolic glycoside in Acanthopanax senticosus. OBJECTIVE This study was performed to investigate whether Syringin could protect high glucose-induced bone marrow mesenchymal stem cells (BMSCs) injury, cell senescence, and osteoporosis by inhibiting JAK2/STAT3 signaling. METHODS BMSCs isolated from both the tibia and femur of mice were induced for osteogenesis. The cell senescence was induced using the high glucose medium. The cells were treated with 10 and 100 μmol/l Syringin. Immunohistochemistry staining was performed to determine the β-galactosidase (SA-β-gal) levels in differentially treated BMSCs. MTT assay and flow cytometry analysis were also performed to assess cell viability and cell cycle. The level of ROS in cells with different treatment was measured by using flow cytometry with DCF-DA staining. Calcium deposition and mineralized matrices were detected with alizarin red and ALP staining, respectively. Osteogenesis related genes OCN, ALP, Runx2, and BMP-2 were detected by RT-PCR. Levels of senescence-related proteins including p53 and p21, as well as JAK2, p-JAK2, STAT3, and p-STAT3 were detected by Western blot analysis. RESULTS Syringin treatment reversed the phenotypes of senescence caused by high glucose in BMSCs, including the arrest of G0/G1 cell cycle, enhanced SA-β-gal activity, and impaired cell growth. Syringin also decreased the elevated ROS production and the levels of p53, p21, and JAK2/STAT3 signaling activation. In addition, Syringin also enhanced the osteogenic potential determined by ARS and ALP staining, as well as increasing OCN, ALP, Runx2, and BMP-2 expressions. CONCLUSION Syringin protects high glucose-induced BMSC injury, cell senescence, and osteoporosis by inhibiting JAK2/STAT3 signaling.
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Affiliation(s)
- Yu-Cong Zou
- Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine, Department of Rehabilitation, Zhuhai 519020, China
| | - Kai Gao
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Bao-Tao Cao
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Xiao-Li He
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Wei Zheng
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Xiao-Fei Wang
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Yu-Fu Li
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Feng Li
- Third Hospital of Shijiazhuang, Department of Orthopedic Surgery, HeBei Province 510000, China
| | - Hua-Jun Wang
- Jinan University, The First Affiliated Hospital, Department of Bone and Joint Surgery and Sports Medicine Center, Guangzhou, 510630 China
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Brochu BM, Sturm SR, Kawase De Queiroz Goncalves JA, Mirsky NA, Sandino AI, Panthaki KZ, Panthaki KZ, Nayak VV, Daunert S, Witek L, Coelho PG. Advances in Bioceramics for Bone Regeneration: A Narrative Review. Biomimetics (Basel) 2024; 9:690. [PMID: 39590262 PMCID: PMC11592113 DOI: 10.3390/biomimetics9110690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/24/2024] [Accepted: 11/02/2024] [Indexed: 11/28/2024] Open
Abstract
Large osseous defects resulting from trauma, tumor resection, or fracture render the inherent ability of the body to repair inadequate and necessitate the use of bone grafts to facilitate the recovery of both form and function of the bony defect sites. In the United States alone, a large number of bone graft procedures are performed yearly, making it an essential area of investigation and research. Synthetic grafts represent a potential alterative to autografts due to their patient-specific customizability, but currently lack widespread acceptance in the clinical space. Early in their development, non-autologous bone grafts composed of metals such as stainless steel and titanium alloys were favorable due to their biocompatibility, resistance to corrosion, mechanical strength, and durability. However, since their inception, bioceramics have also evolved as viable alternatives. This review aims to present an overview of the fundamental prerequisites for tissue engineering devices using bioceramics as well as to provide a comprehensive account of their historical usage and significant advancements over time. This review includes a summary of commonly used manufacturing techniques and an evaluation of their use as drug carriers and bioactive coatings-for therapeutic ion/drug release, and potential avenues to further enhance hard tissue regeneration.
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Affiliation(s)
- Baylee M. Brochu
- University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Savanah R. Sturm
- University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | | | | | | | - Kayaan Zubin Panthaki
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Karl Zubin Panthaki
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Vasudev Vivekanand Nayak
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Lukasz Witek
- Biomaterials Division, NYU Dentistry, 345 E. 24th St., Room 806, New York, NY 10010, USA
- Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY 11201, USA
- Hansjörg Wyss Department of Plastic Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Paulo G. Coelho
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Division of Plastic Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Wang Y, Sun Y, Yang B, Li J, Liang C. The effect and mechanism of liraglutide on the biological functions of BMSCs in diabetic patients. Oral Dis 2024; 30:5160-5174. [PMID: 38501359 DOI: 10.1111/odi.14931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 03/20/2024]
Abstract
OBJECTIVES To investigate the effect of liraglutide on osteogenesis in human alveolar bone marrow mesenchymal stem cells (BMSCs) and the influence of liraglutide on implant-bone integration in rats with T2DM. SUBJECTS AND METHODS Extracting BMSCs from the alveoli of diabetic patients treated with insulin. BMSCs were treated with different concentrations of liraglutide. Osteogenesis and the underlying mechanism were investigated via ALP detection, ALP staining, Alizarin Red S staining, Western blotting, and RT-PCR. Liraglutide was given to Wistar and GK rats after implantation, and new bone formation around the implants was analyzed via micro-CT. Implant-bone integration in rats was investigated via toluidine blue staining. RESULTS Liraglutide enhanced osteogenesis in BMSCs via the BMP2/Smad/Runx2 signaling pathway. The optimal concentration of liraglutide that promoted osteogenesis was 10-8 mol/L. At concentrations higher than 10-7 mol/L, liraglutide had a negative effect on BMSCs. At a concentration of 10-8 mol/L liraglutide, BMSCs and diabetes mellitus-bone marrow stromal cells (DM-BMSCs) showed optimal osteogenesis. Liraglutide promoted implant-bone integration and new bone formation in Wistar and GK rats. CONCLUSIONS Liraglutide not only promotes osteogenesis of BMSCs in normoglycemic individuals but also enhances osteogenesis of BMSCs in diabetic patients treated with insulin and enhances osseointegration in rats.
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Affiliation(s)
- Yao Wang
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yujie Sun
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Bo Yang
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Jun Li
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Chao Liang
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
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Zhang H, Jin C, Hua J, Chen Z, Gao W, Xu W, Zhou L, Shan L. Roles of Microenvironment on Mesenchymal Stem Cells Therapy for Osteoarthritis. J Inflamm Res 2024; 17:7069-7079. [PMID: 39377043 PMCID: PMC11457791 DOI: 10.2147/jir.s475617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/21/2024] [Indexed: 10/09/2024] Open
Abstract
Osteoarthritis (OA) induced microenvironmental alterations are a common and unavoidable phenomenon that greatly exacerbate the pathologic process of OA. Imbalances in the synthesis and degradation of cartilage extracellular matrix (ECM) have been reported to be associated with an adverse microenvironment. Stem cell therapy is a promising treatment for OA, and mesenchymal stem cells (MSCs) are the main cell sources for this therapy. With multispectral differentiation and immunomodulation, MSCs can effectively regulate the microenvironment of articular cartilage, ameliorate inflammation, promote regeneration of damaged cartilage, and ultimately alleviate OA symptoms. However, the efficacy of MSCs in the treatment of OA is greatly influenced by articular cavity microenvironments. This article reviews the five microenvironments of OA articular cavity, including inflammatory microenvironment, senescence microenvironment, hypoxic microenvironment, high glucose microenvironment and high lipid environment, focus on the positive and negative effects of OA microenvironments on the fate of MSCs. In this regard, we emphasize the mechanisms of the current use of MSCs in OA treatment, as well as its limitations and challenges.
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Affiliation(s)
- Haiyan Zhang
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chaoying Jin
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Jiaqing Hua
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenxin Gao
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Wenting Xu
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Letian Shan
- The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
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Huang Y, Wang J, Jiang C, Zheng M, Han M, Fang Q, Liu Y, Li R, Zhong L, Li Z. ANXA2 promotes osteogenic differentiation and inhibits cellular senescence of periodontal ligament cells (PDLCs) in high glucose conditions. PeerJ 2024; 12:e18064. [PMID: 39308808 PMCID: PMC11416082 DOI: 10.7717/peerj.18064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Background Periodontal ligament cells (PDLCs) are a major component of the periodontal ligament and have an important role in the regeneration of periodontal tissue and maintenance of homeostasis. High glucose can affect the activity and function of PDLCs in a variety of ways; therefore, it is particularly important to find ways to alleviate the effects of high glucose on PDLCs. Annexin A2 (ANXA2) is a calcium- and phospholipid-binding protein involved in a variety of cellular functions and processes, including cellular cytokinesis, cytophagy, migration, and proliferation. Aim The aim of this study was to exploring whether ANXA2 attenuates the deleterious effects of high glucose on PDLCs and promotes osteogenic differentiation capacity. Methods and results Osteogenic differentiation potential, cellular senescence, oxidative stress, and cellular autophagy were detected. Culturing PDLCs with medium containing different glucose concentrations (CTRL, 8 mM, 10 mM, 25 mM, and 40 mM) revealed that high glucose decreased the protein expression of ANXA2 (p < 0.0001). In addition, high glucose decreased the osteogenic differentiation potential of PDLCs as evidenced by decreased calcium deposition (p = 0.0003), lowered ALP activity (p = 0.0010), and a decline in the expression of osteogenesis-related genes (p = 0.0008). Moreover, β-Galactosidase staining and expression of p16, p21 and p53 genes showed that it increased cellular senescence in PDLCs (p < 0.0001). Meanwhile high glucose increased oxidative stress in PDLCs as shown by ROS (p < 0.0001). However, these damages caused by high glucose were inhibited after the addition of 1 µM recombinant ANXA2 (rANXA2), and we found that rANXA2 enhanced autophagy in PDLCs under high glucose conditions. Conclusions and discussion Therefore, our present study demonstrates that alterations in ANXA2 under high glucose conditions may be a factor in the decreased osteogenic differentiation potential of PDLCs. Meanwhile, ANXA2 is associated with autophagy, oxidative stress, and cellular senescence under high glucose conditions.
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Affiliation(s)
- Yanlin Huang
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Jiaye Wang
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Chunhui Jiang
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Minghe Zheng
- Department of Stomatology, No.904 Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Jiangsu Province, Wuxi, China
| | - Mingfang Han
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Qian Fang
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Yizhao Liu
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Ru Li
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Liangjun Zhong
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Zehui Li
- Hangzhou Normal University, Zhejiang, China
- Department of Stomatology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
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Abd El-Lateef HM, Ali LS, Qahl SH, Binjawhar DN, Fayad E, Alghamdi MA, Altalhi SA, Al-Salmi FA, Shabana ES, Radwan KH, Youssef I, Shaaban S, Rashwan HM, El-Sawah SG. Therapeutic effect of N, N-Diphenyl-1,4-phenylenediamine and adipose-derived stem cells coadministration on diabetic cardiomyopathy in type 1 diabetes mellitus-rat model. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2024; 341:647-657. [PMID: 38594572 DOI: 10.1002/jez.2810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 02/23/2024] [Accepted: 03/08/2024] [Indexed: 04/11/2024]
Abstract
Type 1 diabetes stem-cell-based treatment approach is among the leading therapeutic strategies for treating cardiac damage owing to the stem cells' regeneration capabilities. Mesenchymal stem cells derived from adipose tissue (AD-MSCs) have shown great potential in treating diabetic cardiomyopathy (DCM). Herein, we explored the antioxidant-supporting role of N, N'-diphenyl-1,4-phenylenediamine (DPPD) in enhancing the MSCs' therapeutic role in alleviating DCM complications in heart tissues of type 1 diabetic rats. Six male albinos Wistar rat groups have been designed into the control group, DPPD (250 mg/kg, i.p.) group, diabetic-untreated group, and three diabetic rat groups treated with either AD-MSCs (1 × 106 cell/rat, i.v.) or DPPD or both. Interestingly, all three treated diabetic groups exhibited a significant decrease in serum glucose, HbA1c, heart dysfunction markers (lactate dehydrogenase and CK-MP) levels, and lipid profile fractions (except for HDL-C), as well as some cardiac oxidative stress (OS) levels (MDA, AGEs, XO, and ROS). On the contrary, serum insulin, C-peptide, and various cardiac antioxidant levels (GSH, GST, CAT, SOD, TAC, and HO-1), beside viable cardiac cells (G0/G1%), were markedly elevated compared with the diabetic untreated group. In support of these findings, the histological assay reflected a marked enhancement in the cardiac tissues of all diabetic-treated groups, with obvious excellency of the AD-MSCs + DPPD diabetic-treated group. Such results strongly suggested the great therapeutic potentiality of either DPPD or AD-MSCs single injection in enhancing the cardiac function of diabetic rats, with a great noted enhancement superiority of DPPD and AD-MSCs coadministration.
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Affiliation(s)
- Hany M Abd El-Lateef
- Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
- Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
| | - Lashin S Ali
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Physiology Department, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Safa H Qahl
- Department of Biological Science, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Dalal N Binjawhar
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Maha A Alghamdi
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Sarah A Altalhi
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Fawziah A Al-Salmi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - El Shaimaa Shabana
- Fellow of Biochemistry, Genetic Unit, Children Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Kholoud H Radwan
- Department of Biochemistry, Horus University in Egypt HUE, Damietta, Egypt
| | - Ibrahim Youssef
- Department of Chemistry, College of Science, Mansoura University, Mansoura, Egypt
- Neuroradiology and Neuro-intervention Section, Department of Radiology, UTSW Medical Center, Dallas, USA
| | - Saad Shaaban
- Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia
- Department of Chemistry, College of Science, Mansoura University, Mansoura, Egypt
| | - Hanan M Rashwan
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Shady G El-Sawah
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
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11
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Alexander M, Cho E, Gliozheni E, Salem Y, Cheung J, Ichii H. Pathology of Diabetes-Induced Immune Dysfunction. Int J Mol Sci 2024; 25:7105. [PMID: 39000211 PMCID: PMC11241249 DOI: 10.3390/ijms25137105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.
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Affiliation(s)
- Michael Alexander
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Eric Cho
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Eiger Gliozheni
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Yusuf Salem
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Joshua Cheung
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
| | - Hirohito Ichii
- Division of Transplantation, Department of Surgery, University of California, Irvine, CA 92868, USA
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12
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Wei Y, Zheng Z, Zhang Y, Sun J, Xu S, Di X, Ding X, Ding G. Regulation of mesenchymal stem cell differentiation by autophagy. Open Med (Wars) 2024; 19:20240968. [PMID: 38799254 PMCID: PMC11117459 DOI: 10.1515/med-2024-0968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/20/2024] [Accepted: 04/17/2024] [Indexed: 05/29/2024] Open
Abstract
Autophagy, a process that isolates intracellular components and fuses them with lysosomes for degradation, plays an important cytoprotective role by eliminating harmful intracellular substances and maintaining cellular homeostasis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity for self-renewal that can give rise to a subset of tissues and therefore have potential in regenerative medicine. However, a variety of variables influence the biological activity of MSCs following their proliferation and transplantation in vitro. The regulation of autophagy in MSCs represents a possible mechanism that influences MSC differentiation properties under the right microenvironment, affecting their regenerative and therapeutic potential. However, a deeper understanding of exactly how autophagy is mobilized to function as well as clarifying the mechanisms by which autophagy promotes MSCs differentiation is still needed. Here, we review the current literature on the complex link between MSCs differentiation and autophagy induced by various extracellular or intracellular stimuli and the molecular targets that influence MSCs lineage determination, which may highlight the potential regulation of autophagy on MSCs' therapeutic capacity, and provide a broader perspective on the clinical application of MSCs in the treatment of a wide range of diseases.
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Affiliation(s)
- Yanan Wei
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Zejun Zheng
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Ying Zhang
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Jinmeng Sun
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Shuangshuang Xu
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Xinsheng Di
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Xiaoling Ding
- Clinical Competency Training Center, Shandong Second Medical University, Weifang, 261053, Shandong, China
| | - Gang Ding
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, Shandong, China
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13
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Niknam B, Azizsoltani A, Heidari N, Tokhanbigli S, Alavifard H, Haji Valili M, Amani D, Asadzadeh Aghdaei H, Hashemi SM, Baghaei K. A Simple High Yield Technique for Isolation of Wharton's Jelly-derived Mesenchymal Stem Cell. Avicenna J Med Biotechnol 2024; 16:95-103. [PMID: 38618506 PMCID: PMC11007369 DOI: 10.18502/ajmb.v16i2.14860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/25/2023] [Indexed: 04/16/2024] Open
Abstract
Background The isolation of Mesenchymal Stem Cells (MSCs) from various tissues is possible, with the umbilical cord emerging as a competitive alternative to bone marrow. In order to fulfill the demands of cell therapy, it is essential to generate stem cells on a clinical scale while minimizing time, cost, and contamination. Here is a simple and effective protocol for isolating MSC from Wharton's Jelly (WJ-MSC) using the explant method with various supplements. Methods Utilizing the explant method, small fragments of Wharton's jelly from the human umbilical cord were cultured in a flask. The multipotency of the isolated cells, were confirmed by their differentiation ability to osteocyte and adipocyte. Additionally, the immunophenotyping of WJ-MSCs showed positive expression of CD73, CD90, and CD105, while remaining negative for hematopoietic markers CD34 and CD45, meeting the criteria for WJ-MSC identification. Following that, to evaluate cells' proliferative capacity, various supplements, including basic Fibroblast Growth Factor (bFGF), Non-Essential amino acids (NEA), and L-Glutamine (L-Gln) were added to either alpha-Minimal Essential Medium (α-MEM) or Dulbecco's Modified Eagle's Medium-F12 (DMEM-F12), as the basic culture media. Results WJ-MSCs isolated by the explant method were removed from the tissue after seven days and transferred to the culture medium. These cells differentiated into adipocyte and osteocyte lineages, expressing CD73, CD90, and CD105 positively and CD34 and CD45 negatively. The results revealed that addition of bFGF to α-MEM or DMEMF12 media significantly increased the proliferation of MSCs when compared to the control group. However, there were no significant differences observed when NEA or LGln were added. Conclusion Although bFGF considerably enhances cell proliferation, our study demonstrates that MSCs can grow and expand when properly prepared Wharton's jelly tissues of the human umbilical cord.
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Affiliation(s)
- Bahare Niknam
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Azizsoltani
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Haji Valili
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davar Amani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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14
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Hussein N, Meade J, Pandit H, Jones E, El-Gendy R. Characterisation and Expression of Osteogenic and Periodontal Markers of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) from Diabetic Knee Joints. Int J Mol Sci 2024; 25:2851. [PMID: 38474098 DOI: 10.3390/ijms25052851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents a significant health problem globally and is linked to a number of complications such as cardiovascular disease, bone fragility and periodontitis. Autologous bone marrow mesenchymal stem cells (BM-MSCs) are a promising therapeutic approach for bone and periodontal regeneration; however, the effect of T2DM on the expression of osteogenic and periodontal markers in BM-MSCs is not fully established. Furthermore, the effect of the presence of comorbidities such as diabetes and osteoarthritis on BM-MSCs is also yet to be investigated. In the present study, BM-MSCs were isolated from osteoarthritic knee joints of diabetic and nondiabetic donors. Both cell groups were compared for their clonogenicity, proliferation rates, MSC enumeration and expression of surface markers. Formation of calcified deposits and expression of osteogenic and periodontal markers were assessed after 1, 2 and 3 weeks of basal and osteogenic culture. Diabetic and nondiabetic BM-MSCs showed similar clonogenic and growth potentials along with comparable numbers of MSCs. However, diabetic BM-MSCs displayed lower expression of periostin (POSTN) and cementum protein 1 (CEMP-1) at Wk3 osteogenic and Wk1 basal cultures, respectively. BM-MSCs from T2DM patients might be suitable candidates for stem cell-based therapeutics. However, further investigations into these cells' behaviours in vitro and in vivo under inflammatory environments and hyperglycaemic conditions are still required.
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Affiliation(s)
- Nancy Hussein
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds LS9 7TF, UK
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Josephine Meade
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds LS9 7TF, UK
| | - Hemant Pandit
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds LS9 7TF, UK
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Leeds LS9 7TF, UK
| | - Reem El-Gendy
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds LS9 7TF, UK
- Department of Oral Pathology, Faculty of Dentistry, Suez Canal University, Ismailia 41522, Egypt
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15
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Ahmadzadeh F, Esmaili M, Ehsan Enderami S, Ghasemi M, Azadeh H, Abediankenari S. Epigallocatechin-3-gallate maintains Th1/Th2 response balance and mitigates type-1 autoimmune diabetes induced by streptozotocin through promoting the effect of bone-marrow-derived mesenchymal stem cells. Gene 2024; 894:148003. [PMID: 37977318 DOI: 10.1016/j.gene.2023.148003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/01/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
Stem-cell-based therapy is one of the most promising therapeutic strategies owing to its regenerative and immunomodulatory properties. Epigallocatechin-3-gallate (EGCG), a known antioxidant and anti-inflammatory agent, has beneficial effects on cellular protection. We aimed to elucidate the feasibility of using EGCG, along with bone marrow-derived mesenchymal stem cells (BM-MSCs), to improve pancreatic damage through their immune regulatory functions in an experimental model of type 1 diabetes mellitus (T1DM) induced by multiple injections of streptozotocin (STZ). BM-MSCs were isolated from C57BL/6 mice and characterized. The diabetic groups were treated intraperitoneally with PBS, MSCs, EGCG, and a combination of MSCs and EGCG. Real-time PCR assays showed that MSCs with EGCG modulated T-bet and GATA-3 expression and upregulated the mRNA levels of Foxp-3 more efficiently. Analyses of spleen-isolated lymphocytes revealed that combinational treatment pronouncedly increased regulatory cytokines and decreased pro-inflammatory cytokines and splenocyte proliferation. The histopathological assessment demonstrated that co-treatment significantly reduced insulitis and recovered pancreatic islet morphology. Furthermore, the combination of MSCs and EGCG is associated with downregulated blood glucose and enhanced insulin levels. Therefore, combined therapy with EGCG and MSCs holds clinical potential for treating T1DM through synergetic effects in maintaining the Th1/Th2 response balance and promoting the regeneration of damaged pancreatic tissues.
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Affiliation(s)
- Fatemeh Ahmadzadeh
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mozhgan Esmaili
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Ehsan Enderami
- Immunogenetics Research Center, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Ghasemi
- Department of Pathology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hossein Azadeh
- Department of Internal Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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16
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Lu J, Zhang L, Zhu N, Wang D, Xie F, Qin M, Wang Y. High glucose levels delay the senescence of stem cells from human exfoliated deciduous teeth by suppressing autophagy. Arch Oral Biol 2024; 157:105851. [PMID: 37992563 DOI: 10.1016/j.archoralbio.2023.105851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/29/2023] [Accepted: 11/14/2023] [Indexed: 11/24/2023]
Abstract
OBJECTIVE In this study, we aimed to investigate the effects of varying glucose concentrations on the proliferation and senescence of stem cells from human exfoliated deciduous teeth (SHED) compared to human bone marrow-derived mesenchymal stem cells (hBMSC), and preliminarily clarify the difference of glucose metabolism between SHED and hBMSC. DESIGN We cultured SHED and hBMSC in the presence of increasing glucose concentrations to study the role of glucose in cell viability, proliferation, and senescence. Gene expression related to the stemness of mesenchymal stem cells was evaluated using real-time quantitative reverse transcription-polymerase chain reaction. In addition, glucose consumption, lactic acid production, oxidative phosphorylation, and glycolysis were measured to analyze glucose metabolism and expression of autophagy-related markers, including microtubule-associated proteins 1 A/1B light chain 3 B and p62. RESULTS While a high glucose level (4.5 g/L) promoted the proliferation of both SHED and hBMSC, it delayed senescence in SHED via autophagy inhibition but accelerated hBMSC senescence. In contrast to that in hBMSC, glycolysis in SHED was enhanced under the high-glucose culture condition. CONCLUSIONS The glycometabolism of SHED and hBMSC differed, and a high glucose culture medium was more favorable for SHED.
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Affiliation(s)
- Jinjin Lu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Lixin Zhang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Ningxin Zhu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Dan Wang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Fei Xie
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Man Qin
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Yuanyuan Wang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China.
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17
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Abu-El-Rub E, Almahasneh F, Khasawneh RR, Alzu'bi A, Ghorab D, Almazari R, Magableh H, Sanajleh A, Shlool H, Mazari M, Bader NS, Al-Momani J. Human mesenchymal stem cells exhibit altered mitochondrial dynamics and poor survival in high glucose microenvironment. World J Stem Cells 2023; 15:1093-1103. [PMID: 38179215 PMCID: PMC10762524 DOI: 10.4252/wjsc.v15.i12.1093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases. Diabetes mellitus (DM) is a frequently diagnosed chronic disease characterized by hyperglycemia which initiates many multisystem complications in the long-run. DM patients can benefit from MSCs transplantation to curb down the pathological consequences associated with hyperglycemia persistence and restore the function of damaged tissues. MSCs therapeutic outcomes are found to last for short period of time and ultimately these regenerative cells are eradicated and died in DM disease model. AIM To investigate the impact of high glucose or hyperglycemia on the cellular and molecular characteristics of MSCs. METHODS Human adipose tissue-derived MSCs (hAD-MSCs) were seeded in low (5.6 mmol/L of glucose) and high glucose (25 mmol/L of glucose) for 7 d. Cytotoxicity, viability, mitochondrial dynamics, and apoptosis were deplored using specific kits. Western blotting was performed to measure the protein expression of phosphatidylinositol 3-kinase (PI3K), TSC1, and mammalian target of rapamycin (mTOR) in these cells. RESULTS hAD-MSCs cultured in high glucose for 7 d demonstrated marked decrease in their viability, as shown by a significant increase in lactate dehydrogenase (P < 0.01) and a significant decrease in Trypan blue (P < 0.05) in these cells compared to low glucose control. Mitochondrial membrane potential, indicated by tetramethylrhodamine ethyl ester (TMRE) fluorescence intensity, and nicotinamide adenine dinucleotide (NAD+)/NADH ratio were significantly dropped (P < 0.05 for TMRE and P < 0.01 for NAD+/NADH) in high glucose exposed hAD-MSCs, indicating disturbed mitochondrial function. PI3K protein expression significantly decreased in high glucose culture MSCs (P < 0.05 compared to low glucose) and it was coupled with significant upregulation in TSC1 (P < 0.05) and downregulation in mTOR protein expression (P < 0.05). Mitochondrial complexes I, IV, and V were downregulated profoundly in high glucose (P < 0.05 compared to low glucose). Apoptosis was induced as a result of mitochondrial impairment and explained the poor survival of MSCs in high glucose. CONCLUSION High glucose impaired the mitochondrial dynamics and regulatory proteins in hAD-MSCs ensuing their poor survival and high apoptosis rate in hyperglycemic microenvironment.
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Affiliation(s)
- Ejlal Abu-El-Rub
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan.
| | - Fatimah Almahasneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ramada R Khasawneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ayman Alzu'bi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Doaa Ghorab
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rawan Almazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Huthaifa Magableh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ahmad Sanajleh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Haitham Shlool
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Mohammad Mazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Noor S Bader
- Department of Basic Medical Sciences, Yarmouk University, Irbid 21163, Jordan
| | - Joud Al-Momani
- Department of Basic Medical Sciences, Yarmouk University, Irbid 21163, Jordan
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18
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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19
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Tao H, Liu Q, Zeng A, Song L. Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging. Int Immunopharmacol 2023; 121:110497. [PMID: 37329808 DOI: 10.1016/j.intimp.2023.110497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023]
Abstract
Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.
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Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Qianglin Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, PR China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
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20
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Todosenko N, Khaziakhmatova O, Malashchenko V, Yurova K, Bograya M, Beletskaya M, Vulf M, Mikhailova L, Minchenko A, Soroko I, Khlusov I, Litvinova L. Adipocyte- and Monocyte-Mediated Vicious Circle of Inflammation and Obesity (Review of Cellular and Molecular Mechanisms). Int J Mol Sci 2023; 24:12259. [PMID: 37569635 PMCID: PMC10418857 DOI: 10.3390/ijms241512259] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Monocytes play a key role in the development of metabolic syndrome, and especially obesity. Given the complex features of their development from progenitor cells, whose regulation is mediated by their interactions with bone marrow adipocytes, the importance of a detailed study of the heterogeneous composition of monocytes at the molecular and systemic levels becomes clear. Research argues for monocytes as indicators of changes in the body's metabolism and the possibility of developing therapeutic strategies to combat obesity and components of metabolic syndrome based on manipulations of the monocyte compound of the immune response. An in-depth study of the heterogeneity of bone-marrow-derived monocytes and adipocytes could provide answers to many questions about the pathogenesis of obesity and reveal their therapeutic potential.
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Affiliation(s)
- Natalia Todosenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Olga Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Vladimir Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Kristina Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Maria Bograya
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Maria Beletskaya
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Maria Vulf
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Larisa Mikhailova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Anastasia Minchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Irina Soroko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
| | - Igor Khlusov
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
- Laboratory of Cellular and Microfluidic Technologies, Siberian State Medical University, 2, Moskovskii Trakt, 634050 Tomsk, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236001 Kaliningrad, Russia; (N.T.); (O.K.); (V.M.); (K.Y.); (M.B.); (M.B.); (M.V.); (L.M.); (A.M.); (I.S.); (I.K.)
- Laboratory of Cellular and Microfluidic Technologies, Siberian State Medical University, 2, Moskovskii Trakt, 634050 Tomsk, Russia
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21
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Luo M, Zhao Z, Yi J. Osteogenesis of bone marrow mesenchymal stem cell in hyperglycemia. Front Endocrinol (Lausanne) 2023; 14:1150068. [PMID: 37415664 PMCID: PMC10321525 DOI: 10.3389/fendo.2023.1150068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023] Open
Abstract
Diabetes mellitus (DM) has been shown to be a clinical risk factor for bone diseases including osteoporosis and fragility. Bone metabolism is a complicated process that requires coordinated differentiation and proliferation of bone marrow mesenchymal stem cells (BMSCs). Owing to the regenerative properties, BMSCs have laid a robust foundation for their clinical application in various diseases. However, mounting evidence indicates that the osteogenic capability of BMSCs is impaired under high glucose conditions, which is responsible for diabetic bone diseases and greatly reduces the therapeutic efficiency of BMSCs. With the rapidly increasing incidence of DM, a better understanding of the impacts of hyperglycemia on BMSCs osteogenesis and the underlying mechanisms is needed. In this review, we aim to summarize the current knowledge of the osteogenesis of BMSCs in hyperglycemia, the underlying mechanisms, and the strategies to rescue the impaired BMSCs osteogenesis.
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Affiliation(s)
- Meng Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jianru Yi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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22
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Liao KM, Chen CJ, Luo WJ, Hsu CW, Yu SL, Yang PC, Su KY. Senomorphic effect of diphenyleneiodonium through AMPK/MFF/DRP1 mediated mitochondrial fission. Biomed Pharmacother 2023; 162:114616. [PMID: 37004322 DOI: 10.1016/j.biopha.2023.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
With an aging population and the numerous health impacts associated with old age, the identification of anti-aging drugs has become an important new research direction. Although mitochondria have been recognized to affect aging, anti-aging drugs specifically targeting the mitochondria are less well characterized. In this study, diphenyleneiodonium (DPI) was identified as a potential senomorphic drug that functions by promoting mitochondrial fission. DPI significantly reduced the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and increased the number of proliferating Ki-67 positive cells in BrdU or irradiation stress-induced senescent NIH3T3 cells or IMR90 cells and mouse embryonic fibroblasts (MEFs) replicative senescent cells. Cell cycle arrest genes and senescence-associated secretory phenotype (SASP) factors were downregulated with DPI treatment. In addition, the oxygen consumption rate (OCR) of mitochondrial respiration showed that DPI significantly reduced senescence-associated hyper OCR. Mechanistically, DPI promoted mitochondrial fission by enhancing AMPK/MFF phosphorylation and DRP1 mitochondrial translocation. Inhibition of DRP1 by Mdivi-1 abolished DPI-induced mitochondrial fission and the anti-senescence phenotype. Importantly, Eighty-eight-week-old mice treated with DPI had significantly reduced numbers of SA-β-gal positive cells and reduced expression of cell cycle arrest genes and SASP factors in their livers and kidneys. Pathological and functional assays showed DPI treatment not only reduced liver fibrosis and immune cell infiltration but also improved aged-related physical impairments in aged mice. Taken together, our study identified a potential anti-aging compound that exerts its effects through modulation of mitochondrial morphology.
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23
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Wang S, Wang J, Wang S, Tao R, Yi J, Chen M, Zhao Z. mTOR Signaling Pathway in Bone Diseases Associated with Hyperglycemia. Int J Mol Sci 2023; 24:ijms24119198. [PMID: 37298150 DOI: 10.3390/ijms24119198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 06/12/2023] Open
Abstract
The interplay between bone and glucose metabolism has highlighted hyperglycemia as a potential risk factor for bone diseases. With the increasing prevalence of diabetes mellitus worldwide and its subsequent socioeconomic burden, there is a pressing need to develop a better understanding of the molecular mechanisms involved in hyperglycemia-mediated bone metabolism. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that senses extracellular and intracellular signals to regulate numerous biological processes, including cell growth, proliferation, and differentiation. As mounting evidence suggests the involvement of mTOR in diabetic bone disease, we provide a comprehensive review of its effects on bone diseases associated with hyperglycemia. This review summarizes key findings from basic and clinical studies regarding mTOR's roles in regulating bone formation, bone resorption, inflammatory responses, and bone vascularity in hyperglycemia. It also provides valuable insights into future research directions aimed at developing mTOR-targeted therapies for combating diabetic bone diseases.
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Affiliation(s)
- Shuangcheng Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Jiale Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shuangwen Wang
- West China School of Medicine, Sichuan University, Chengdu 610041, China
| | - Ran Tao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Jianru Yi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Miao Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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24
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Su HY, Yang JJ, Zou R, An N, Chen XC, Yang C, Yang HJ, Yao CW, Liu HF. Autophagy in peritoneal fibrosis. Front Physiol 2023; 14:1187207. [PMID: 37256065 PMCID: PMC10226653 DOI: 10.3389/fphys.2023.1187207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/03/2023] [Indexed: 06/01/2023] Open
Abstract
Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.
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25
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Goutas A, Outskouni Z, Papathanasiou I, Georgakopoulou A, Karpetas GE, Gonos ES, Trachana V. The establishment of mitotic errors-driven senescence depends on autophagy. Redox Biol 2023; 62:102701. [PMID: 37094517 PMCID: PMC10149375 DOI: 10.1016/j.redox.2023.102701] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 04/26/2023] Open
Abstract
We and others have reported that senescence onset is accompanied by genomic instability that is evident by several defects, such as aneuploidy or erroneous mitosis features. Here, we report that these defects also appear in young cells upon oxidative insult. We provide evidence that these errors could be the consequence of oxidative stress (OS)- either exogenous or senescence-associated - overriding the spindle assembly checkpoint (SAC). Young cells treated with Η2Ο2 as well as older cells fail to maintain mitotic arrest in the presence of spindle poisons and a significant higher percentage of them have supernumerary centrosomes and centrosome related anomalous characteristics. We also report that aging is escorted by expression modifications of SAC components, and especially of Bub1b/BubR1. Bub1b/BubR1 has been previously reported to decrease naturally upon aging. Here, we show that there is an initial increase in Bub1b/BubR1 levels, feasibly as part of the cells' response against OS-driven genomic instability, that is followed by its autophagy dependent degradation. This provides an explanation that was missing regarding the molecular entity responsible for the downregulation of Bub1b/BubR1 upon aging, especially since it is well established, by us and others, that the proteasome function decays as cells age. These results, not only serve the previously reported notion of a shift from proteasome to autophagy-dependent degradation upon aging, but also provide a mechanistic insight for mitotic errors-driven senescence. We believe that our conclusions deepen our understanding regarding the homeostatic function of autophagy that serves the establishment of senescence as a barrier against cellular transformation.
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Affiliation(s)
- Andreas Goutas
- Department of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, 41500, Greece.
| | - Zozo Outskouni
- Department of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, 41500, Greece.
| | - Ioanna Papathanasiou
- Department of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, 41500, Greece.
| | - Aphrodite Georgakopoulou
- Hematology Department, Hematopoietic Cell Transplant (HCT) Unit, Gene and Cell Therapy Center, George Papanikolaou Hospital, Thessaloniki, 57010, Greece.
| | - Georgios E Karpetas
- Department of Medical Informatics, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, 41500, Greece.
| | - Efstathios S Gonos
- Hellenic Pasteur Institute, Athens, 11521, Greece; Institute of Biology, Medical Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece.
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, 41500, Greece.
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26
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Ye P, Feng L, Zhang D, Li R, Wen Y, Tong X, Shi S, Dong C. Metformin Ameliorates D-Galactose-Induced Senescent Human Bone Marrow-Derived Mesenchymal Stem Cells by Enhancing Autophagy. Stem Cells Int 2023; 2023:1429642. [PMID: 37035446 PMCID: PMC10079386 DOI: 10.1155/2023/1429642] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/16/2023] [Accepted: 03/11/2023] [Indexed: 04/04/2023] Open
Abstract
Human bone marrow-derived mesenchymal stem cells (hBMSCs) are promising candidates for stem cell therapy in clinical trials. Applications of hBMSCs in clinical therapy are limited by cellular senescence due to long-term ex vivo expansion. Metformin, an oral hypoglycemic drug for type 2 diabetes, has been shown to have antiaging effects. However, the mechanisms of metformin in antiaging treatment remain controversial. Here, we used D-galactose (D-gal) to establish an appropriate model of senescent hBMSCs to explore the antiaging effects of metformin. Following metformin treatment with a low concentration range, senescence phenotypes induced by D-gal significantly changed, including generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and cell cycle arrest. In contrast, no apparent change was found in unsenescent hBMSCs. Furthermore, the results show that activation of 5'AMP-activated protein kinase (AMPK) by metformin enhances cell autophagy in senescent hBMSCs. These findings suggest that metformin exerts antiaging function within the low concentration range by enhancing autophagy and exhibits potential benefits for clinical stem cell therapy by ameliorating the ex vivo replicative senescence of hBMSCs.
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Affiliation(s)
- Pingting Ye
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Lei Feng
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Dan Zhang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Ruihao Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Yixuan Wen
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Xiaohan Tong
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Shuo Shi
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
| | - Chunyan Dong
- Department of Oncology, Shanghai East Hospital, School of Medicine, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200120, China
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27
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The Potential of Senescence as a Target for Developing Anticancer Therapy. Int J Mol Sci 2023; 24:ijms24043436. [PMID: 36834846 PMCID: PMC9961771 DOI: 10.3390/ijms24043436] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Senescence occurs in response to various stimuli. Senescence has attracted attention because of its potential use in anticancer therapy as it plays a tumor-suppressive role. It also promotes tumorigeneses and therapeutic resistance. Since senescence can induce therapeutic resistance, targeting senescence may help to overcome therapeutic resistance. This review provides the mechanisms of senescence induction and the roles of the senescence-associated secretory phenotype (SASP) in various life processes, including therapeutic resistance and tumorigenesis. The SASP exerts pro-tumorigenic or antitumorigenic effects in a context-dependent manner. This review also discusses the roles of autophagy, histone deacetylases (HDACs), and microRNAs in senescence. Many reports have suggested that targeting HDACs or miRNAs could induce senescence, which, in turn, could enhance the effects of current anticancer drugs. This review presents the view that senescence induction is a powerful method of inhibiting cancer cell proliferation.
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28
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Luo G, Wosinski P, Salazar-Noratto GE, Bensidhoum M, Bizios R, Marashi SA, Potier E, Sheng P, Petite H. Glucose Metabolism: Optimizing Regenerative Functionalities of Mesenchymal Stromal Cells Postimplantation. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:47-61. [PMID: 35754335 DOI: 10.1089/ten.teb.2022.0063] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Mesenchymal stromal cells (MSCs) are considered promising candidates for regenerative medicine applications. Their clinical performance postimplantation, however, has been disappointing. This lack of therapeutic efficacy is most likely due to suboptimal formulations of MSC-containing material constructs. Tissue engineers, therefore, have developed strategies addressing/incorporating optimized cell, microenvironmental, biochemical, and biophysical cues/stimuli to enhance MSC-containing construct performance. Such approaches have had limited success because they overlooked that maintenance of MSC viability after implantation for a sufficient time is necessary for MSCs to develop their regenerative functionalities fully. Following a brief overview of glucose metabolism and regulation in MSCs, the present literature review includes recent pertinent findings that challenge old paradigms and notions. We hereby report that glucose is the primary energy substrate for MSCs, provides precursors for biomass generation, and regulates MSC functions, including proliferation and immunosuppressive properties. More importantly, glucose metabolism is central in controlling in vitro MSC expansion, in vivo MSC viability, and MSC-mediated angiogenesis postimplantation when addressing MSC-based therapies. Meanwhile, in silico models are highlighted for predicting the glucose needs of MSCs in specific regenerative medicine settings, which will eventually enable tissue engineers to design viable and potent tissue constructs. This new knowledge should be incorporated into developing novel effective MSC-based therapies. Impact statement The clinical use of mesenchymal stromal cells (MSCs) has been unsatisfactory due to the inability of MSCs to survive and be functional after implantation for sufficient periods to mediate directly or indirectly a successful regenerative tissue response. The present review summarizes the endeavors in the past, but, most importantly, reports the latest findings that elucidate underlying mechanisms and identify glucose metabolism as the crucial parameter in MSC survival and the subsequent functions pertinent to new tissue formation of importance in tissue regeneration applications. These latest findings justify further basic research and the impetus for developing new strategies to improve the modalities and efficacy of MSC-based therapies.
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Affiliation(s)
- Guotian Luo
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Pauline Wosinski
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Giuliana E Salazar-Noratto
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Morad Bensidhoum
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Rena Bizios
- Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, Texas, USA
| | - Sayed-Amir Marashi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Esther Potier
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
| | - Puyi Sheng
- Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hervé Petite
- Université Paris Cité, CNRS, INSERM, B3OA, Paris, France.,École Nationale Vétérinaire d'Alfort, B3OA, Maisons-Alfort, France
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29
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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30
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Klabklai P, Phetfong J, Tangporncharoen R, Isarankura-Na-Ayudhya C, Tawonsawatruk T, Supokawej A. Annexin A2 Improves the Osteogenic Differentiation of Mesenchymal Stem Cells Exposed to High-Glucose Conditions through Lessening the Senescence. Int J Mol Sci 2022; 23:ijms232012521. [PMID: 36293376 PMCID: PMC9604334 DOI: 10.3390/ijms232012521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/06/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Osteoporosis is frequently found in chronic diabetic patients, and it results in an increased risk of bone fractures occurring. The underlying mechanism of osteoporosis in diabetic patients is still largely unknown. Annexin A2 (ANXA2), a family of calcium-binding proteins, has been reported to be involved in many biological process including bone remodeling. This study aimed to investigate the role of ANXA2 in mesenchymal stem cells (MSCs) during in vitro osteoinduction under high-glucose concentrations. Osteogenic gene expression, calcium deposition, and cellular senescence were determined. The high-glucose conditions reduced the osteogenic differentiation potential of the MSCs along with the lower expression of ANXA2. Moreover, the high-glucose conditions increased the cellular senescence of the MSCs as determined by senescence-associated β-galactosidase staining and the expression of p16, p21, and p53 genes. The addition of recombinant ANXA2 could recover the glucose-induced deterioration of the osteogenic differentiation of the MSCs and ameliorate the glucose-induced cellular senescence of the MSCs. A Western blot analysis revealed an increase in p53 and phosphorylated p53 (Ser 15), which was decreased by recombinant ANXA2 in MSC osteoblastic differentiation under high-glucose conditions. Our study suggested that the alteration of ANXA2 in high-glucose conditions may be one of the plausible factors in the deterioration of bones in diabetic patients by triggering cellular senescence.
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Affiliation(s)
- Parin Klabklai
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhonpathom 73170, Thailand
| | - Jitrada Phetfong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhonpathom 73170, Thailand
| | - Rattanawan Tangporncharoen
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhonpathom 73170, Thailand
| | - Chartchalerm Isarankura-Na-Ayudhya
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Nakhonpathom 73170, Thailand
| | - Tulyapruek Tawonsawatruk
- Department of Orthopaedics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Aungkura Supokawej
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhonpathom 73170, Thailand
- Correspondence: ; Fax: +66-2-441-4380
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31
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Huang W, Hickson LJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 2022; 18:611-627. [PMID: 35922662 PMCID: PMC9362342 DOI: 10.1038/s41581-022-00601-z] [Citation(s) in RCA: 531] [Impact Index Per Article: 177.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2022] [Indexed: 01/10/2023]
Abstract
Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.
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Affiliation(s)
- Weijun Huang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - LaTonya J Hickson
- Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
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32
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Yang YP, Lai WY, Lin TW, Lin YY, Chien Y, Tsai YC, Tai HY, Wang CL, Liu YY, Huang PI, Chen YW, Lo WL, Wang CY. Autophagy reprogramming stem cell pluripotency and multiple-lineage differentiation. J Chin Med Assoc 2022; 85:667-671. [PMID: 35385421 DOI: 10.1097/jcma.0000000000000728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The cellular process responsible for the degradation of cytosolic proteins and subcellular organelles in lysosomes was termed "autophagy." This process occurs at a basal level in most tissues as part of tissue homeostasis that redounds to the regular turnover of components inside cytoplasm. The breakthrough in the autophagy field is the identification of key players in the autophagy pathway, compounded under the name "autophagy-related genes" (ATG) encoding for autophagy effector proteins. Generally, the function of autophagy can be classified into two divisions: intracellular clearance of defective macromolecules and organelles and generation of degradation products. Therapeutic strategies using stem cell-based approach come as a promising therapy and develop rapidly recently as stem cells have high self-renewability and differentiation capability as known as mesenchymal stem cells (MSCs). They are defined as adherent fibroblast-like population with the abilities to self-renew and multi-lineage differentiate into osteogenic, adipogenic, and chondrogenic lineage cells. To date, they are the most extensively applied adult stem cells in clinical trials. The properties of MSCs, such as immunomodulation, neuroprotection, and tissue repair pertaining to cell differentiation, processes to replace lost, or damaged cells, for aiding cell repair and revival. Autophagy has been viewed as a remarkable mechanism for maintaining homeostasis, ensuring the adequate function and survival of long-lived stem cells. In addition, authophagy also plays a remarkable role in protecting stem cells against cellular stress when the stem cell regenerative capacity is harmed in aging and cellular degeneration. Understanding the under-explored mechanisms of MSC actions and expanding the spectrum of their clinical applications may improve the utility of the MSC-based therapeutic approach in the future.
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Affiliation(s)
- Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Wei-Yi Lai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Tzu-Wei Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ying Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Ching Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hsiao-Yun Tai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chia-Lin Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yung-Yang Liu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-I Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Wei Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wen-Liang Lo
- Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chien-Ying Wang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Physical Education and Health, University of Taipei, Taipei, Taiwan, ROC
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Ruiz-Aparicio PF, Vernot JP. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities. J Pers Med 2022; 12:jpm12050716. [PMID: 35629139 PMCID: PMC9147878 DOI: 10.3390/jpm12050716] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 12/17/2022] Open
Abstract
Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
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Affiliation(s)
- Paola Fernanda Ruiz-Aparicio
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
| | - Jean-Paul Vernot
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
- Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia
- Correspondence:
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Yang Y, Lei T, Bi W, Xiao Z, Zhang X, Du H. The combined therapy of mesenchymal stem cell transplantation and resveratrol for diabetes: Future applications and challenges. Life Sci 2022; 301:120563. [PMID: 35460708 DOI: 10.1016/j.lfs.2022.120563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) is a worldwide chronic epidemic disease of impaired glucose metabolism. Transplantation of mesenchymal stem cells (MSCs) is considered a promising emerging treatment strategy for diabetes. However, the harsh internal environment of DM patients can inhibit the treatment effects of transplanted MSCs. Fortunately, this adverse effect can be reversed by resveratrol (Res). Therefore, we investigated and summarized relevant studies on the combined treatment of diabetes with MSCs and resveratrol. This review presents the therapeutic effects of this combination therapy strategy on DM in glycemic control, anti-inflammatory, anti-oxidative stress and anti-fibrotic. Moreover, this review explained the mechanisms of MSCs and resveratrol in diabetes treatment from 3 aspects, including promoting cell survival and inhibiting apoptosis, inhibiting histiocyte fibrosis, and improving glucose metabolism. These findings help to understand in-depth mechanisms of the treatment of DM and help to propose a potential treatment strategy for DM and its complications.
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Affiliation(s)
- Yanjie Yang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Tong Lei
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Wangyu Bi
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Zhuangzhuang Xiao
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Xiaoshuang Zhang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Hongwu Du
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
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35
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Cho JH, Lee JH, Lee KM, Lee CK, Shin DM. BMP-2 Induced Signaling Pathways and Phenotypes: Comparisons Between Senescent and Non-senescent Bone Marrow Mesenchymal Stem Cells. Calcif Tissue Int 2022; 110:489-503. [PMID: 34714366 DOI: 10.1007/s00223-021-00923-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/04/2021] [Indexed: 10/20/2022]
Abstract
The use of BMP-2 in orthopedic surgery is limited by uncertainty surrounding its effects on the differentiation of mesenchymal stem cells (MSCs) and how this is affected by cellular aging. This study compared the effects of recombinant human BMP-2 (rhBMP-2) on osteogenic and adipogenic differentiation between senescent and non-senescent MSCs. Senescent and non-senescent MSCs were cultured in osteogenic and adipogenic differentiation medium containing various concentrations of rhBMP-2. The phenotypes of these cells were compared by performing a calcium assay, adipogenesis assay, staining, real-time PCR, western blotting, and microarray analysis. rhBMP-2 induced osteogenic differentiation to a lesser extent (P < 0.001 and P = 0.005 for alkaline phosphatase activity and Ca2+ release) in senescent MSCs regardless of dose-dependent increase in both cells. However, the induction of adipogenic differentiation by rhBMP-2 was comparable between them. There was no difference between these two groups of cells in the adipogenesis assay (P = 0.279) and their expression levels of PPARγ were similar. Several genes such as CHRDL1, NOG, SMAD1, SMAD7, and FST encoding transcription factors were proposed to underlie the different responses of senescent and non-senescent MSCs to rhBMP-2 in microarray analyses. Furthermore, inflammatory, adipogenic, or cell death-related signaling pathways such as NF-kB or p38-MAPK pathways were upregulated by BMP-2 in senescent MSCs, whereas bone forming signaling pathways involving BMP, SMAD, and TGF- ß were upregulated in non-senescent MSCs as expected. This phenomenon explains bone forming dominance by non-senescent MSCs and possible frequent complications such as seroma, osteolysis, or neuritis in senescent MSCs during BMP-2 use in orthopedic surgery.
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Affiliation(s)
- Jae Hwan Cho
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hyup Lee
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Boramae-ro 5-gil, Dongjak-Gu, Seoul, Republic of Korea.
| | - Kyung Mee Lee
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Choon-Ki Lee
- Department of Orthopedic Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Dong-Myung Shin
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea
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36
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Adipose-Derived Stem Cells Preincubated with Green Tea EGCG Enhance Pancreatic Tissue Regeneration in Rats with Type 1 Diabetes through ROS/Sirt1 Signaling Regulation. Int J Mol Sci 2022; 23:ijms23063165. [PMID: 35328586 PMCID: PMC8951845 DOI: 10.3390/ijms23063165] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Type 1 diabetes stem-cell-based therapy is one of the best therapeutic approaches for pancreatic damage treatment due to stem cell tissue regeneration. Epigallocatechin gallate (EGCG) is one of the active components found in green tea. Experimental results suggest that EGCG shows beneficial effects on cell protection. This study explores whether a better pancreatic regeneration therapeutic effect could be found in mesenchymal stem cells pretreated with EGCG compared to stem cells without EGCG pretreatment. A cell model confirmed that adipose-derived stem cells (ADSC) incubated with EGCG increase cell viability under high-glucose (HG) stress. This is due to survival marker p-Akt expression. In an animal model, type 1 diabetes induced the activation of several pathological signals, including islet size reduction, extracellular fibrotic collagen deposition, oxidative stress elevation, survival pathway suppression, apoptosis signaling induction, and Sirt1 antioxidant pathway downregulation. Ordinary ADSC transplantation slightly improved the above pathological signals. Further, EGCG-pretreated ADSC transplantation significantly improved the above pathological conditions. Taken together, EGCG-pretreated ADSCs show clinical potential in the treatment of patients with type 1 diabetes through the regeneration of damaged pancreatic tissues.
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37
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Aaron N, Costa S, Rosen CJ, Qiang L. The Implications of Bone Marrow Adipose Tissue on Inflammaging. Front Endocrinol (Lausanne) 2022; 13:853765. [PMID: 35360075 PMCID: PMC8962663 DOI: 10.3389/fendo.2022.853765] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/16/2022] [Indexed: 12/30/2022] Open
Abstract
Once considered an inert filler of the bone cavity, bone marrow adipose tissue (BMAT) is now regarded as a metabolically active organ that plays versatile roles in endocrine function, hematopoiesis, bone homeostasis and metabolism, and, potentially, energy conservation. While the regulation of BMAT is inadequately understood, it is recognized as a unique and dynamic fat depot that is distinct from peripheral fat. As we age, bone marrow adipocytes (BMAds) accumulate throughout the bone marrow (BM) milieu to influence the microenvironment. This process is conceivably signaled by the secretion of adipocyte-derived factors including pro-inflammatory cytokines and adipokines. Adipokines participate in the development of a chronic state of low-grade systemic inflammation (inflammaging), which trigger changes in the immune system that are characterized by declining fidelity and efficiency and cause an imbalance between pro-inflammatory and anti-inflammatory networks. In this review, we discuss the local effects of BMAT on bone homeostasis and the hematopoietic niche, age-related inflammatory changes associated with BMAT accrual, and the downstream effect on endocrine function, energy expenditure, and metabolism. Furthermore, we address therapeutic strategies to prevent BMAT accumulation and associated dysfunction during aging. In sum, BMAT is emerging as a critical player in aging and its explicit characterization still requires further research.
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Affiliation(s)
- Nicole Aaron
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pharmacology, Columbia University, New York, NY, United States
| | - Samantha Costa
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, United States
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States
| | - Clifford J. Rosen
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, United States
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States
- *Correspondence: Clifford J. Rosen, ; Li Qiang,
| | - Li Qiang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pathology, Columbia University, New York, NY, United States
- *Correspondence: Clifford J. Rosen, ; Li Qiang,
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38
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The Effect of Diabetes Mellitus on IGF Axis and Stem Cell Mediated Regeneration of the Periodontium. Bioengineering (Basel) 2021; 8:bioengineering8120202. [PMID: 34940355 PMCID: PMC8698546 DOI: 10.3390/bioengineering8120202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 11/29/2021] [Indexed: 11/16/2022] Open
Abstract
Periodontitis and diabetes mellitus (DM) are two of the most common and challenging health problems worldwide and they affect each other mutually and adversely. Current periodontal therapies have unpredictable outcome in diabetic patients. Periodontal tissue engineering is a challenging but promising approach that aims at restoring periodontal tissues using one or all of the following: stem cells, signalling molecules and scaffolds. Mesenchymal stem cells (MSCs) and insulin-like growth factor (IGF) represent ideal examples of stem cells and signalling molecules. This review outlines the most recent updates in characterizing MSCs isolated from diabetics to fully understand why diabetics are more prone to periodontitis that theoretically reflect the impaired regenerative capabilities of their native stem cells. This characterisation is of utmost importance to enhance autologous stem cells based tissue regeneration in diabetic patients using both MSCs and members of IGF axis.
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Nunes ADC, Weigl M, Schneider A, Noureddine S, Yu L, Lahde C, Saccon TD, Mitra K, Beltran E, Grillari J, Kirkland JL, Tchkonia T, Robbins PD, Masternak MM. miR-146a-5p modulates cellular senescence and apoptosis in visceral adipose tissue of long-lived Ames dwarf mice and in cultured pre-adipocytes. GeroScience 2021; 44:503-518. [PMID: 34825304 PMCID: PMC8811002 DOI: 10.1007/s11357-021-00490-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/09/2021] [Indexed: 12/31/2022] Open
Abstract
MicroRNAs (miRNAs) are potent regulators of multiple biological processes. Previous studies have demonstrated that miR-146a-5p increases in normal mice during aging, while long-living Ames dwarf (df/df) mice maintain youthful levels of this miRNA. The aim of this study was to elucidate the involvement of miR-146a-5p in modulating cellular senescence and apoptosis in visceral adipose tissue of df/df mice and cultured pre-adipocytes. To test the effects of miR-146a-5p overexpression on visceral adipose tissue, wild-type, and df/df mice, were treated with miRNA-negative control-base and df/df were transfected with 4 or 8 µg/g of a miR-146a-5p mimetic, respectively. Effects of miR-146a-5p overexpression were also evaluated in 3T3-L1 cells cultured under high and normal glucose conditions. Treatment with miR-146a-5p mimetic increased cellular senescence and inflammation and decreased pro-apoptotic factors in visceral adipose tissue of df/df mice. The miR-146a-5p mimetic induced similar effects in 3T3-L1 cells cultivated at normal but not high glucose levels. Importantly, 3T3-L1 HG cells in high glucose conditions showed significantly higher expression of miR-146a-5p than 3T3-L1 grown in normal glucose conditions. These results indicate that miR-146a-5p can be a marker for cellular senescence. This miRNA represents one of the significant SASP factors that if not precisely regulated, can accentuate inflammatory responses and stimulate senescence in surrounding non-senescent cells. The role of miR-146a-5p is different in healthy versus stressed cells, suggesting potential effects of this miRNA depend on overall organismal health, aging, and metabolic state.
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Affiliation(s)
- Allancer D C Nunes
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Moritz Weigl
- Ludwig Boltzmann Institute of Traumatology in Cooperation With AUVA, Vienna, Austria
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Sarah Noureddine
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
| | - Lin Yu
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
| | - Collin Lahde
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
| | | | - Kunal Mitra
- Biomedical Engineering, Florida Tech, Melbourne, FL, 32901, USA
| | - Esther Beltran
- Florida Space Institute, University of Central Florida, Orlando, FL, 32826, USA
| | - Johannes Grillari
- Ludwig Boltzmann Institute of Traumatology in Cooperation With AUVA, Vienna, Austria
- Institute of Molecular Biotechnology, BOKU-University of Natural Resources and Life Sciences, Vienna, Austria
| | - James L Kirkland
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, 55905, USA
| | - Tamara Tchkonia
- Robert and Arlene Kogod Center On Aging, Mayo Clinic, Rochester, MN, 55905, USA
| | - Paul D Robbins
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Michal M Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA.
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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40
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Casado-Díaz A, Rodríguez-Ramos Á, Torrecillas-Baena B, Dorado G, Quesada-Gómez JM, Gálvez-Moreno MÁ. Flavonoid Phloretin Inhibits Adipogenesis and Increases OPG Expression in Adipocytes Derived from Human Bone-Marrow Mesenchymal Stromal-Cells. Nutrients 2021; 13:4185. [PMID: 34836440 PMCID: PMC8623874 DOI: 10.3390/nu13114185] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Phloretin (a flavonoid abundant in apple), has antioxidant, anti-inflammatory, and glucose-transporter inhibitory properties. Thus, it has interesting pharmacological and nutraceutical potential. Bone-marrow mesenchymal stem cells (MSC) have high differentiation capacity, being essential for maintaining homeostasis and regenerative capacity in the organism. Yet, they preferentially differentiate into adipocytes instead of osteoblasts with aging. This has a negative impact on bone turnover, remodeling, and formation. We have evaluated the effects of phloretin on human adipogenesis, analyzing MSC induced to differentiate into adipocytes. Expression of adipogenic genes, as well as genes encoding OPG and RANKL (involved in osteoclastogenesis), protein synthesis, lipid-droplets formation, and apoptosis, were studied. Results showed that 10 and 20 µM phloretin inhibited adipogenesis. This effect was mediated by increasing beta-catenin, as well as increasing apoptosis in adipocytes, at late stages of differentiation. In addition, this chemical increased OPG gene expression and OPG/RANKL ratio in adipocytes. These results suggest that this flavonoid (including phloretin-rich foods) has interesting potential for clinical and regenerative-medicine applications. Thus, such chemicals could be used to counteract obesity and prevent bone-marrow adiposity. That is particularly useful to protect bone mass and treat diseases like osteoporosis, which is an epidemic worldwide.
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Affiliation(s)
- Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Ángel Rodríguez-Ramos
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Bárbara Torrecillas-Baena
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, CIBERFES, 14071 Córdoba, Spain;
| | - José Manuel Quesada-Gómez
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición—GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, 14004 Córdoba, Spain; (Á.R.-R.); (B.T.-B.); (J.M.Q.-G.); (M.Á.G.-M.)
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Chen M, Jing D, Ye R, Yi J, Zhao Z. PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy. Stem Cell Res Ther 2021; 12:566. [PMID: 34736532 PMCID: PMC8567548 DOI: 10.1186/s13287-021-02628-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/16/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. METHODS We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. RESULTS Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. CONCLUSION In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.
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Affiliation(s)
- Miao Chen
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China
| | - Dian Jing
- Department of Orthodontics, Shanghai Ninth People's Hospital, Collage of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Ye
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China
| | - Jianru Yi
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.
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Marin C, Tuts J, Luyten FP, Vandamme K, Kerckhofs G. Impaired soft and hard callus formation during fracture healing in diet-induced obese mice as revealed by 3D contrast-enhanced computed tomography imaging. Bone 2021; 150:116008. [PMID: 33992820 DOI: 10.1016/j.bone.2021.116008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 11/21/2022]
Abstract
The impact of diabetes mellitus on bone fracture healing is clinically relevant as the patients experience delayed fracture healing. Even though efforts have been made to understand the detrimental effects of type 2 diabetes mellitus (T2DM) on the fracture healing process, the exact mechanisms causing the pathophysiological outcomes remain unclear. The aim of this study was to assess alterations in bone fracture healing (tibial fracture surgery, intramedullary pinning) of diet-induced obese (DIO) mice, and to investigate the in vitro properties of osteochondroprogenitors derived from the diabetic micro-environment. High-resolution contrast-enhanced microfocus X-ray computed tomography (CE-CT) enabled a simultaneous 3D assessment of the amount and spatial distribution of the regenerated soft and hard tissues during fracture healing and revealed that osteogenesis as well as chondrogenesis are altered in DIO mice. Compared to age-matched lean controls, DIO mice presented a decreased bone volume fraction and increased callus volume and adiposity at day 14 post-fracture. Of note, bone turnover was found altered in DIO mice relative to controls, evidenced by decreased blood serum osteocalcin and increased serum CTX levels. The in vitro data revealed that not only the osteogenic and adipogenic differentiation of periosteum-derived cells (PDCs) were altered by hyperglycemic (HG) conditions, but also the chondrogenic differentiation. Elevated PPARγ expression in HG conditions confirmed the observed increase in differentiated adipocytes in vitro. Finally, chondrogenesis-related genes COL2 and COL10 were downregulated for PDCs treated with HG medium, confirming that chondrogenic differentiation is compromised in vitro and suggesting that this may affect callus formation and maturation during the fracture healing process in vivo. Altogether, these results provide novel insights into the alterations of long bone fracture repair and suggest a link between HG-induced dysfunctionality of osteochondroprogenitor differentiation and fracture healing impairment under T2DM conditions.
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Affiliation(s)
- Carlos Marin
- Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Prometheus - Division of Skeletal Tissue Engineering Leuven, KU Leuven, Leuven, Belgium; Biomaterials - BIOMAT, Department of Oral Health Sciences, KU Leuven, Leuven, Belgium
| | - Jolien Tuts
- Biomaterials - BIOMAT, Department of Oral Health Sciences, KU Leuven, Leuven, Belgium
| | - Frank P Luyten
- Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Prometheus - Division of Skeletal Tissue Engineering Leuven, KU Leuven, Leuven, Belgium
| | - Katleen Vandamme
- Prometheus - Division of Skeletal Tissue Engineering Leuven, KU Leuven, Leuven, Belgium; Biomaterials - BIOMAT, Department of Oral Health Sciences, KU Leuven, Leuven, Belgium
| | - Greet Kerckhofs
- Prometheus - Division of Skeletal Tissue Engineering Leuven, KU Leuven, Leuven, Belgium; Department of Material Science and Engineering, KU Leuven, Leuven, Belgium; Biomechanics lab, Institute of Mechanics, Materials, and Civil Engineering, UCLouvain, Louvain-la-Neuve, Belgium; Institute for Experimental and Clinical Research, UCLouvain, Woluwe, Belgium.
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Grønningsæter IS, Reikvam H, Aasebø E, Bartaula-Brevik S, Hernandez-Valladares M, Selheim F, Berven FS, Tvedt TH, Bruserud Ø, Hatfield KJ. Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity. J Pers Med 2021; 11:jpm11080779. [PMID: 34442423 PMCID: PMC8399694 DOI: 10.3390/jpm11080779] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evaluated the effects of chloroquine on cell viability and proliferation of acute myeloid leukemia acute myeloid leukemia (AML) cells derived from 81 AML patients. Our results show that chloroquine decreased AML cell viability and proliferation for the majority of patients. Furthermore, a subgroup of AML patients showed a greater susceptibility to chloroquine, and using hierarchical cluster analysis, we identified 99 genes upregulated in this patient subgroup, including several genes related to leukemogenesis. The combination of chloroquine with low-dose cytarabine had an additive inhibitory effect on AML cell proliferation. Finally, a minority of patients showed increased extracellular constitutive mediator release in the presence of chloroquine, which was associated with strong antiproliferative effects of chloroquine as well as cytarabine. We conclude that chloroquine has antileukemic activity and should be further explored as a therapeutic drug against AML in combination with other cytotoxic or metabolic drugs; however, due to the patient heterogeneity, chloroquine therapy will probably be effective only for selected patients.
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Affiliation(s)
- Ida Sofie Grønningsæter
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
- Department of Medicine, Akershus University Hospital, N-1478 Lørenskog, Norway
| | - Håkon Reikvam
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
- Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway;
| | - Elise Aasebø
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
- The Proteomics Facility of the University of Bergen (PROBE), Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway; (M.H.-V.); (F.S.); (F.S.B.)
| | - Sushma Bartaula-Brevik
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
| | - Maria Hernandez-Valladares
- The Proteomics Facility of the University of Bergen (PROBE), Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway; (M.H.-V.); (F.S.); (F.S.B.)
- The Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway
| | - Frode Selheim
- The Proteomics Facility of the University of Bergen (PROBE), Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway; (M.H.-V.); (F.S.); (F.S.B.)
- The Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway
| | - Frode S. Berven
- The Proteomics Facility of the University of Bergen (PROBE), Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway; (M.H.-V.); (F.S.); (F.S.B.)
- The Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway
| | - Tor Henrik Tvedt
- Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway;
- Department of Hematology, Oslo University Hospital—The National Hospital, N-0372 Oslo, Norway
| | - Øystein Bruserud
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
- Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway;
- Correspondence: (Ø.B.); (K.J.H.)
| | - Kimberley Joanne Hatfield
- Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; (I.S.G.); (H.R.); (E.A.); (S.B.-B.)
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, N-5009 Bergen, Norway
- Correspondence: (Ø.B.); (K.J.H.)
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Brunetti G, D'Amato G, De Santis S, Grano M, Faienza MF. Mechanisms of altered bone remodeling in children with type 1 diabetes. World J Diabetes 2021; 12:997-1009. [PMID: 34326950 PMCID: PMC8311475 DOI: 10.4239/wjd.v12.i7.997] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/17/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Bone loss associated with type 1 diabetes mellitus (T1DM) begins at the onset of the disease, already in childhood, determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life. The mechanisms underlying diabetic bone fragility are not yet completely understood. Hyperglycemia and insulin deficiency can affect the bone cells functions, as well as the bone marrow fat, thus impairing the bone strength, geometry, and microarchitecture. Several factors, like insulin and growth hormone/insulin-like growth factor 1, can control bone marrow mesenchymal stem cell commitment, and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover. Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects. The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.
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Affiliation(s)
- Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University "A. Moro" of Bari, Bari 70125, Italy
| | - Gabriele D'Amato
- Department of Women’s and Children’s Health, ASL Bari, Neonatal Intensive Care Unit, Di Venere Hospital, Bari 70124, Italy
| | - Stefania De Santis
- Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari 70126, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, Univ Bari, Bari 70124, Italy
| | - Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University "A.Moro", Bari 70124, Italy
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Zhang F, Wang K, Gao F, Xuan Y, Liu X, Zhang Z. Resveratrol Pretreatment Improved Heart Recovery Ability of Hyperglycemic Bone Marrow Stem Cells Transplantation in Diabetic Myocardial Infarction by Down-Regulating MicroRNA-34a. Front Pharmacol 2021; 12:632375. [PMID: 34177568 PMCID: PMC8223511 DOI: 10.3389/fphar.2021.632375] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/18/2021] [Indexed: 01/16/2023] Open
Abstract
AIM: To examine the effect of resveratrol (RSV) on bone marrow mesenchymal stem cells (BMSCs) under hyperglycemic conditions and on BMSCs transplantation in diabetic rats with myocardial infarction (MI). METHODS:In vitro, BMSCs were isolated from 3-week-old male Sprague Dawley (SD) rats and cultured under hyperglycemic conditions for up to 28 days. Cell viability was analyzed by cell counting kit-8 (CCK-8) assays. The expression of miR-34a was measured by RT-qPCR. Western blotting was used to examine the protein expression of SIRT1, P21, P16, VEGF and HIF-1α. A senescence-associated β-galactosidase assay was used to examine the senescence level of each group. In vivo, a diabetes model was established by feeding rats a high-sugar and high-fat diet for 8 weeks, injecting the animals with streptozotocin (STZ) and continuing high-sugar and high-fat feeding for 4 additional weeks. Then, left anterior descending coronary artery (LAD) cessation was used to established the myocardial infarction (MI) models. Each group of rats was transplanted with differentially preconditioned BMSCs after myocardial infarction. Ultrasound was used to analyze cardiac function 1 and 3 weeks after the operation, and frozen heart sections were used for immunohistochemical analysis, Masson staining and CD31 measurement. In addition, ELISA analysis of serum cytokine levels was performed. RESULTS: This study showed that the viability of BMSCs cultured under hyperglycemic conditions was decreased, the cells became senescent. Besides, an obviously increased in the expression of miR-34a was detected. Moreover, RSV preconditioning reduced the expression of miR-34a in BMSCs after high glucose stimulation and rejuvenated BMSCs under hyperglycemic conditions. Further analysis showed that the transplantation of RSV-BMSCs were benefit to heart recovery following infarction in diabetic rats, promoted proangiogenic factor release and increased arteriole and capillary densities. CONCLUSION: RSV rejuvenated BMSCs after chronic hyperglycemia-induced senescence by interacting with miR-34a and optimized the therapeutic effect of BMSCs on diabetes with myocardial infarction.
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Affiliation(s)
- Fengyun Zhang
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kun Wang
- Department of Cardiology, First People's Hospital of Suqian, Suqian, China
| | - Fei Gao
- Department of Cardiology, Institute of Cardiovascular Research, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yongli Xuan
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiaohong Liu
- Department of Cardiology, Institute of Cardiovascular Research, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Zhuoqi Zhang
- Department of Cardiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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Towards Physiologic Culture Approaches to Improve Standard Cultivation of Mesenchymal Stem Cells. Cells 2021; 10:cells10040886. [PMID: 33924517 PMCID: PMC8069108 DOI: 10.3390/cells10040886] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are of great interest for their use in cell-based therapies due to their multipotent differentiation and immunomodulatory capacities. In consequence of limited numbers following their isolation from the donor tissue, MSCs require extensive expansion performed in traditional 2D cell culture setups to reach adequate amounts for therapeutic use. However, prolonged culture of MSCs in vitro has been shown to decrease their differentiation potential and alter their immunomodulatory properties. For that reason, preservation of these physiological characteristics of MSCs throughout their in vitro culture is essential for improving the efficiency of therapeutic and in vitro modeling applications. With this objective in mind, many studies already investigated certain parameters for enhancing current standard MSC culture protocols with regard to the effects of specific culture media components or culture conditions. Although there is a lot of diversity in the final therapeutic uses of the cells, the primary stage of standard isolation and expansion is imperative. Therefore, we want to review on approaches for optimizing standard MSC culture protocols during this essential primary step of in vitro expansion. The reviewed studies investigate and suggest improvements focused on culture media components (amino acids, ascorbic acid, glucose level, growth factors, lipids, platelet lysate, trace elements, serum, and xenogeneic components) as well as culture conditions and processes (hypoxia, cell seeding, and dissociation during passaging), in order to preserve the MSC phenotype and functionality during the primary phase of in vitro culture.
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van de Vyver M, Powrie YSL, Smith C. Targeting Stem Cells in Chronic Inflammatory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:163-181. [PMID: 33725353 DOI: 10.1007/978-3-030-55035-6_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cell (MSC) dysfunction is a serious complication in ageing and age-related inflammatory diseases such as type 2 diabetes mellitus. Inflammation and oxidative stress-induced cellular senescence alter the immunomodulatory ability of MSCs and hamper their pro-regenerative function, which in turn leads to an increase in disease severity, maladaptive tissue damage and the development of comorbidities. Targeting stem/progenitor cells to restore their function and/or protect them against impairment could thus improve healing outcomes and significantly enhance the quality of life for diabetic patients. This review discusses the dysregulation of MSCs' immunomodulatory capacity in the context of diabetes mellitus and focuses on intervention strategies aimed at MSC rejuvenation. Research pertaining to the potential therapeutic use of either pharmacological agents (NFкB antagonists), natural products (phytomedicine) or biological agents (exosomes, probiotics) to improve MSC function is discussed and an overview of the most pertinent methodological considerations given. Based on in vitro studies, numerous anti-inflammatory agents, antioxidants and biological agents show tremendous potential to revitalise MSCs. An integrated systems approach and a thorough understanding of complete disease pathology are however required to identify feasible candidates for in vivo targeting of MSCs.
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Affiliation(s)
- Mari van de Vyver
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - Yigael S L Powrie
- Department of Medicine, Faculty of Medicine & Health Sciences, Stellenbosch University, Cape Town, South Africa.,Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
| | - Carine Smith
- Department of Physiological Sciences, Science Faculty, Stellenbosch University, Stellenbosch, South Africa
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Jorgensen C, Khoury M. Musculoskeletal Progenitor/Stromal Cell-Derived Mitochondria Modulate Cell Differentiation and Therapeutical Function. Front Immunol 2021; 12:606781. [PMID: 33763061 PMCID: PMC7982675 DOI: 10.3389/fimmu.2021.606781] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/20/2021] [Indexed: 12/24/2022] Open
Abstract
Musculoskeletal stromal cells’ (MSCs’) metabolism impacts cell differentiation as well as immune function. During osteogenic and adipogenic differentiation, BM-MSCs show a preference for glycolysis during proliferation but shift to an oxidative phosphorylation (OxPhos)-dependent metabolism. The MSC immunoregulatory fate is achieved with cell polarization, and the result is sustained production of immunoregulatory molecules (including PGE2, HGF, IL1RA, IL6, IL8, IDO activity) in response to inflammatory stimuli. MSCs adapt their energetic metabolism when acquiring immunomodulatory property and shift to aerobic glycolysis. This can be achieved via hypoxia, pretreatment with small molecule-metabolic mediators such as oligomycin, or AKT/mTOR pathway modulation. The immunoregulatory effect of MSC on macrophages polarization and Th17 switch is related to the glycolytic status of the MSC. Indeed, MSCs pretreated with oligomycin decreased the M1/M2 ratio, inhibited T-CD4 proliferation, and prevented Th17 switch. Mitochondrial activity also impacts MSC metabolism. In the bone marrow, MSCs are present in a quiescent, low proliferation, but they keep their multi-progenitor function. In this stage, they appear to be glycolytic with active mitochondria (MT) status. During MSC expansion, we observed a metabolic shift toward OXPhos, coupled with an increased MT activity. An increased production of ROS and dysfunctional mitochondria is associated with the metabolic shift to glycolysis. In contrast, when MSC underwent chondro or osteoblast differentiation, they showed a decreased glycolysis and inhibition of the pentose phosphate pathway (PPP). In parallel the mitochondrial enzymatic activities increased associated with oxidative phosphorylation enhancement. MSCs respond to damaged or inflamed tissue through the transfer of MT to injured and immune cells, conveying a type of signaling that contributes to the restoration of cell homeostasis and immune function. The delivery of MT into injured cells increased ATP levels which in turn maintained cellular bioenergetics and recovered cell functions. MSC-derived MT may be transferred via tunneling nanotubes to undifferentiated cardiomyocytes and leading to their maturation. In this review, we will decipher the pathways and the mechanisms responsible for mitochondria transfer and activity. The eventual reversal of the metabolic and pro-inflammatory profile induced by the MT transfer will open new avenues for the control of inflammatory diseases.
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Affiliation(s)
- Christian Jorgensen
- Inserm, U1183, Montpellier, France.,Université MONTPELLIER 1, UFR de Médecine, Montpellier, France.,Service d'immuno-Rhumatologie, Hôpital Lapeyronie, Montpellier, France
| | - Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile.,Cells for Cells, Santiago, Chile.,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile
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Li H, Zhu H, Ge T, Wang Z, Zhang C. Mesenchymal Stem Cell-Based Therapy for Diabetes Mellitus: Enhancement Strategies and Future Perspectives. Stem Cell Rev Rep 2021; 17:1552-1569. [PMID: 33675006 DOI: 10.1007/s12015-021-10139-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM), a chronic disorder of carbohydrate metabolism, is characterized by the unbridled hyperglycemia resulted from the impaired ability of the body to either produce or respond to insulin. As a cell-based regenerative therapy, mesenchymal stem cells (MSCs) hold immense potency for curing DM duo to their easy isolation, multi-differentiation potential, and immunomodulatory property. However, despite the promising efficacy in pre-clinical animal models, naive MSC administration fails to exhibit clinically satisfactory therapeutic outcomes, which varies greatly among individuals with DM. Recently, numbers of innovative strategies have been applied to improve MSC-based therapy. Preconditioning, genetic modification, combination therapy and exosome application are representative strategies to maximize the therapeutic benefits of MSCs. Therefore, in this review, we summarize recent advancements in mechanistic studies of MSCs-based treatment for DM, and mainly focus on the novel approaches aiming to improve the anti-diabetic potentials of naive MSCs. Additionally, the potential directions of MSCs-based therapy for DM are also proposed at a glance.
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Affiliation(s)
- Haisen Li
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Ting Ge
- Xinxiang First People's Hospital, Xinxiang 453000, China
| | - Zhifeng Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. .,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China.
| | - Chao Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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Shi L, Han Q, Hong Y, Li W, Gong G, Cui J, Mao M, Liang X, Hu B, Li X, Luo Q, Zhang Y. Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis. Stem Cell Res Ther 2021; 12:147. [PMID: 33632305 PMCID: PMC7905557 DOI: 10.1186/s13287-021-02215-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/07/2021] [Indexed: 02/08/2023] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02215-x.
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Affiliation(s)
- Linli Shi
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China.,Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Qian Han
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China
| | - Yimei Hong
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Weifeng Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Gencheng Gong
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China
| | - Jiangyu Cui
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Mengmeng Mao
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China
| | - Xiaoting Liang
- Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bei Hu
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Xin Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China. .,Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
| | - Qun Luo
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China.
| | - Yuelin Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China. .,Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
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