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Wang J, Jian K, Yang Q, Gu C, Sheng J, Zhou Y, Yin H, Zhang Z, Hua K, Zhang C. Retarding human adipose-derived MSCs senescence and promoting tendon repair using cell sheet engineering with a histone methyltransferase inhibitor. Sci Rep 2025; 15:6198. [PMID: 39979391 PMCID: PMC11842574 DOI: 10.1038/s41598-025-89234-3] [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: 10/29/2024] [Accepted: 02/04/2025] [Indexed: 02/22/2025] Open
Abstract
Mesenchymal stem cell (MSC) holds immense potential as candidates for cell therapy in the treatment of tendon injuries due to their remarkable ability for multiple cell differentiation. However, the proliferative and differentiation capacity of MSCs has been limited by cellular senescence during the process of expanding culture. Therefore, in this study, our aim was to maintain the beneficial properties of MSCs. We found that SETD7, a histone methyltransferase, was upregulated during ex vivo expansion of human adipose-derived mesenchymal stem cells (hAD-MSCs). Pharmacological inhibition of SETD7 with PFI-2 in hAD-MSCs cultures delayed their senescence, as evident by the diminished expression of senescent-associated genes and the maintenance of their proliferation and differentiation capacity. Upon transplantation, cell sheets derived from hAD-MSCs expanded with PFI-2 were better able to accelerate tendon repair. Therefore, the present findings reveal that SETD7 is an important target to improve the expansion of hAD-MSCs by delaying senescence, which is importance for the development of efficient stem cell-based therapeutic approaches.
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Affiliation(s)
- Junjuan Wang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Ke Jian
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China
| | - Qing Yang
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China
| | - Chunyi Gu
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Jiajun Sheng
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Yan Zhou
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Hantian Yin
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Zhihan Zhang
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 310000, China
| | - Kouzhen Hua
- Department of Anatomy, School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, 311300, China.
| | - Can Zhang
- Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, 410082, China.
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2
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Cuevas RA, Hortells L, Chu CC, Wong R, Crane A, Boufford C, Regan C, Moorhead WJ, Bashline MJ, Parwal A, Parise AM, Behzadi P, Brown MJ, Gurkar A, Bruemmer D, Sembrat J, Sultan I, Gleason TG, Billaud M, St. Hilaire C. Non-Canonical TERT Activity Initiates Osteogenesis in Calcific Aortic Valve Disease. Circ Res 2025; 136:403-421. [PMID: 39835393 PMCID: PMC11825275 DOI: 10.1161/circresaha.122.321889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Calcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells. METHODS Human control and calcific aortic valve disease aortic valve leaflets and patient-specific human aortic valve interstitial cells were used in in vivo and in vitro calcification assays. Loss of function experiments in human aortic valve interstitial cells and cells isolated from Tert-/- and Terc-/- mice were used for mechanistic studies. Calcification was assessed in Tert+/+ and Tert-/- mice ex vivo and in vivo. In silico modeling, proximity ligation, and coimmunoprecipitation assays defined novel TERT interacting partners. Chromatin immunoprecipitation and cleavage under targets and tagmentation sequencing defined protein-DNA interactions. RESULTS TERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary human aortic valve interstitial cells. TERT expression increased with osteogenic or inflammatory stimuli, and knockdown or genetic deletion of TERT prevented calcification in vitro and in vivo. Mechanistically, TERT was upregulated via NF-κB (nuclear factor-kappa B) and required to initiate osteogenic reprogramming, independent of its canonical reverse transcriptase activity and the long noncoding RNA TERC. TERT exerts non-canonical osteogenic functions via binding with STAT5 (signal transducer and activator of transcription 5). Depletion or inhibition of STAT5 prevented calcification. STAT5 was found to bind the promoter region of RUNX2 (runt-related transcription factor 2), the master regulator of osteogenic reprogramming. Finally, we demonstrate that TERT and STAT5 are upregulated and colocalized in calcific aortic valve disease tissue compared with control tissue. CONCLUSIONS TERT's non-canonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification.
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Affiliation(s)
- Rolando A. Cuevas
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Luis Hortells
- Cardiovascular Research Group, Department of Medical Biology, Faculty of Health Science, UiT-The Arctic University of Norway, 9019 Tromsø, Norway
| | - Claire C. Chu
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ryan Wong
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alex Crane
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Camille Boufford
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Cailyn Regan
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - William J. Moorhead
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Michael J. Bashline
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aneesha Parwal
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Angelina M. Parise
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Parya Behzadi
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mark J. Brown
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aditi Gurkar
- Aging Institute, Division of Geriatrics, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dennis Bruemmer
- Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - John Sembrat
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Ibrahim Sultan
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Thomas G. Gleason
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Marie Billaud
- Division of Cardiac Surgery, Department of Cardiothoracic Surgery, Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Cynthia St. Hilaire
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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3
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Iskandar M, Xiao Barbero M, Jaber M, Chen R, Gomez-Guevara R, Cruz E, Westerheide S. A Review of Telomere Attrition in Cancer and Aging: Current Molecular Insights and Future Therapeutic Approaches. Cancers (Basel) 2025; 17:257. [PMID: 39858038 PMCID: PMC11764024 DOI: 10.3390/cancers17020257] [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: 11/07/2024] [Revised: 01/09/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. METHODS We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. RESULTS Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson-Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. CONCLUSIONS The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging.
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Affiliation(s)
| | | | | | | | | | | | - Sandy Westerheide
- Department of Molecular Biosciences, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL 33620, USA; (M.I.); (M.X.B.); (M.J.); (R.C.); (R.G.-G.); (E.C.)
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4
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Kambe R, Mitomo K, Ikarashi T, Haketa M, Tashiro K, Furusawa M, Muramatsu T. Localization of Both CD31- and Endomucin-Expressing Vessels in Mouse Dental Pulp. Acta Histochem Cytochem 2024; 57:157-163. [PMID: 39552934 PMCID: PMC11565222 DOI: 10.1267/ahc.24-00009] [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: 01/19/2024] [Accepted: 09/03/2024] [Indexed: 11/19/2024] Open
Abstract
We investigated the localization of both CD31- and endomucin-expressing vessels in mouse dental pulp to elucidate their relationship with dentin formation. The maxillae of C57BL/6 male mice (1, 4, 8, 12, and 56 weeks old) were fixed with 4% paraformaldehyde solution, and cryosections (12-μm-thick) were prepared. Immunofluorescence was performed using anti-CD31 and anti-endomucin antibodies, and calcein labeling was conducted to elucidate relationships with dentin formation. At 1 week, many CD31-expressing (CD31 (+)) and endomucin-expressing (endomucin (+)) vessels were observed throughout the dental papilla. At 4 weeks, CD31 (+) and endomucin (+) vessels decreased in the crown and increased in the root of dental pulp. At 12 weeks, CD31 (+) and endomucin (+) vessels were detected at the root apex, but not in coronal pulp. At 56 weeks, few CD31 (+) and endomucin (+) vessels were observed in dental pulp. Both CD31(+) and endomucin (+) vessels were detected directly beneath calcein-labeled dentin at all sites. These results suggest the presence of CD31 (+) and endomucin (+) vessels in dental pulp and their contribution to dentin formation.
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Affiliation(s)
- Ryo Kambe
- Department of Endodontics, Tokyo Dental College, Tokyo, Japan
| | - Keisuke Mitomo
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan
| | - Takatoshi Ikarashi
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan
| | - Mayuka Haketa
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan
| | - Kentaro Tashiro
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan
| | | | - Takashi Muramatsu
- Department of Operative Dentistry, Cariology and Pulp Biology, Tokyo Dental College, Tokyo, Japan
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5
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Onoki T, Kanczler J, Rawlings A, Smith M, Kim YH, Hashimoto K, Aizawa T, Oreffo ROC. Modulation of osteoblastogenesis by NRF2: NRF2 activation suppresses osteogenic differentiation and enhances mineralization in human bone marrow-derived mesenchymal stromal cells. FASEB J 2024; 38:e23892. [PMID: 39230563 DOI: 10.1096/fj.202400602r] [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: 03/18/2024] [Revised: 07/09/2024] [Accepted: 08/05/2024] [Indexed: 09/05/2024]
Abstract
Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca2+ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.
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Affiliation(s)
- Takahiro Onoki
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Janos Kanczler
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
| | - Andrew Rawlings
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
| | - Melanie Smith
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
| | - Yang-Hee Kim
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
| | - Ko Hashimoto
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Toshimi Aizawa
- Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Richard O C Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK
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6
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Zakaria MF, Sonoda S, Kato H, Ma L, Uehara N, Kyumoto-Nakamura Y, Sharifa MM, Yu L, Dai L, Yamauchi-Tomoda E, Aijima R, Yamaza H, Nishimura F, Yamaza T. Erythropoietin receptor signal is crucial for periodontal ligament stem cell-based tissue reconstruction in periodontal disease. Sci Rep 2024; 14:6719. [PMID: 38509204 PMCID: PMC10954634 DOI: 10.1038/s41598-024-57361-y] [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: 11/11/2023] [Accepted: 03/18/2024] [Indexed: 03/22/2024] Open
Abstract
Alveolar bone loss caused by periodontal disease eventually leads to tooth loss. Periodontal ligament stem cells (PDLSCs) are the tissue-specific cells for maintaining and repairing the periodontal ligament, cementum, and alveolar bone. Here, we investigated the role of erythropoietin receptor (EPOR), which regulates the microenvironment-modulating function of mesenchymal stem cells, in PDLSC-based periodontal therapy. We isolated PDLSCs from patients with chronic periodontal disease and healthy donors, referred to as PD-PDLSCs and Cont-PDLSCs, respectively. PD-PDLSCs exhibited reduced potency of periodontal tissue regeneration and lower expression of EPOR compared to Cont-PDLSCs. EPOR-silencing suppressed the potency of Cont-PDLSCs mimicking PD-PDLSCs, whereas EPO-mediated EPOR activation rejuvenated the reduced potency of PD-PDLSCs. Furthermore, we locally transplanted EPOR-silenced and EPOR-activated PDLSCs into the gingiva around the teeth of ligament-induced periodontitis model mice and demonstrated that EPOR in PDLSCs participated in the regeneration of the periodontal ligament, cementum, and alveolar bone in the ligated teeth. The EPOR-mediated paracrine function of PDLSCs maintains periodontal immune suppression and bone metabolic balance via osteoclasts and osteoblasts in the periodontitis model mice. Taken together, these results suggest that EPOR signaling is crucial for PDLSC-based periodontal regeneration and paves the way for the development of novel options for periodontal therapy.
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Affiliation(s)
- Mhd Fouad Zakaria
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Department of Periodontology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Lan Ma
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yukari Kyumoto-Nakamura
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - M Majd Sharifa
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Liting Yu
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Lisha Dai
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Erika Yamauchi-Tomoda
- Department of Oral and Maxillofacial Radiology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Reona Aijima
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saga University, Saga, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Fusanori Nishimura
- Department of Periodontology, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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7
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Liu K, He X, Zhang Z, Sun T, Chen J, Chen C, Wen W, Ding S, Liu M, Zhou C, Luo B. Highly anisotropic and elastic cellulosic scaffold guiding cell orientation and osteogenic differentiation via topological and mechanical cues. Carbohydr Polym 2023; 321:121292. [PMID: 37739527 DOI: 10.1016/j.carbpol.2023.121292] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/01/2023] [Accepted: 08/10/2023] [Indexed: 09/24/2023]
Abstract
Inspired by the similarity of anisotropic channels in wood to the canals of bone, the elastic wood-derived (EW) scaffolds with anisotropic channels were prepared via simple delignification treatment of natural wood (NW). We hypothesize that the degree of delignification will lead to differences in mechanical properties of scaffolds, which in turn directly affect the behaviors and fate of stem cells. The delignification process did not destroy the anisotropic channel structure of the scaffolds, but endowed the scaffolds with good elasticity and rapid stress relaxation. Interestingly, the micron-scale anisotropic channels of the scaffolds can highly promote the polarization of cells along the direction of channels. We also found that the alkaline phosphatase of EW scaffold can reach to about 13.1 U/gprot, which was about double that of NW scaffold. Moreover, the longer the delignification time, the better the osteogenic activity of the EW scaffolds. We further hypothesize that the osteogenic activity of scaffolds is related to the stress relaxation properties. The immunofluorescence staining showed that when the stress relaxation time of scaffold was shortened to about 10 s, the nuclear ratio of YAP of scaffold increased to 0.22, which well supports our hypothesis.
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Affiliation(s)
- Kun Liu
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Xiangheng He
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Zhaoyu Zhang
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Tianyi Sun
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Jiaqing Chen
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Chunhua Chen
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China
| | - Wei Wen
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China; Engineering Research Center of Artificial Organs and Materials, Ministry of Education, Guangzhou 510632, PR China
| | - Shan Ding
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China; Engineering Research Center of Artificial Organs and Materials, Ministry of Education, Guangzhou 510632, PR China
| | - Mingxian Liu
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China; Engineering Research Center of Artificial Organs and Materials, Ministry of Education, Guangzhou 510632, PR China
| | - Changren Zhou
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China; Engineering Research Center of Artificial Organs and Materials, Ministry of Education, Guangzhou 510632, PR China
| | - Binghong Luo
- Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China; Engineering Research Center of Artificial Organs and Materials, Ministry of Education, Guangzhou 510632, PR China.
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8
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Li X, Jiang Y, Liu X, Fu J, Du J, Luo Z, Xu J, Bhawal UK, Liu Y, Guo L. Mesenchymal stem cell-derived apoptotic bodies alleviate alveolar bone destruction by regulating osteoclast differentiation and function. Int J Oral Sci 2023; 15:51. [PMID: 38040672 PMCID: PMC10692139 DOI: 10.1038/s41368-023-00255-y] [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: 08/21/2023] [Revised: 10/21/2023] [Accepted: 10/22/2023] [Indexed: 12/03/2023] Open
Abstract
Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells (MSCs) are essential for periodontal regeneration. However, the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs. Apoptotic bodies (ABs) are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment, thus we investigated the effects of ABs derived from MSCs on periodontitis. MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h, after which ABs were isolated from the culture supernatant using a multi-filtration system. The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption. miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects. Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p, which interferes with the function of osteoclasts. Additionally, DC-STAMP is a key regulator that mediates membrane infusion. ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes, which mediates the engulfment of ABs by pre-osteoclasts. ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts. Collectively, MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP, which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts, which in turn led to the attenuation of their differentiation and bone resorption. These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.
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Grants
- National Key R&D Program of China (Grant NO. 2022YFC2504200), the National Nature Science Foundation of China (81991504 and 81974149), the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202121), Innovation Research Team Project of Beijing Stomatological Hospital, Capital Medical University (CXTD202202), the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20181501)
- National Nature Science Foundation of China (82201052), Beijing Municipal Administration of Hospitals’ Youth Programme (QML20231505), the Beijing Stomatological Hospital, Capital Medical University Young Scientist Program (NO. YSP202103)
- Beijing Municipal Administration of Hospitals’ Youth Programme (QML20181501), Innovation Foundation of Beijing Stomatological Hospital, Capital Medical University (21-09-18)
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Affiliation(s)
- Xiaoyan Li
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Yiyang Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Xu Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Zhenhua Luo
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
| | - Ujjal Kumar Bhawal
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China.
| | - Lijia Guo
- Department of Orthodontics School of Stomatology, Capital Medical University, Beijing, China.
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9
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Lin Y, Jin L, Yang Y. Periodontal ligament cells from patients with treated stable periodontitis: Characterization and osteogenic differentiation potential. J Periodontal Res 2023; 58:237-246. [PMID: 36567428 DOI: 10.1111/jre.13085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 11/22/2022] [Accepted: 12/12/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVE Periodontal ligament progenitor cells (PDL cells) isolated from patients with inflammatory periodontitis have impaired regenerative capacity, but it is unknown whether this capacity can be recovered upon treatment and stabilization of the periodontal condition. The study aimed to investigate the expression of surface markers and the proliferation and osteogenic potential of PDL cells isolated from patients with treated stable periodontitis (S-PDL cells), periodontally healthy individuals (H-PDL cells), and patients with inflammatory periodontitis (I-PDL cells). METHODS H-PDL, I-PDL, and S-PDL cells were isolated from the extracted teeth of individuals who (1) were periodontally healthy, (2) had inflammatory periodontitis, and (3) had treated stable periodontitis, respectively. The expression levels of surface markers and the proliferative and osteogenic capacities of the PDL cells were assessed. RESULTS PDL cells derived from all three sources exhibited mesenchymal stem cell (MSC) characteristics. They were positive for MSC-related markers and negative for a hematopoiesis-related marker. However, S-PDL cells had higher proliferation rates, higher expression levels of osteogenic markers, higher alkaline phosphatase activity, and more calcium nodules than I-PDL cells. But all of these parameters remained lower in S-PDL cells than in H-PDL cells. CONCLUSIONS S-PDL cells proliferated faster and had greater osteogenic potential than I-PDL cells, although these values remained lower than those in H-PDL cells.
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Affiliation(s)
- Yifan Lin
- Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Lijian Jin
- Periodontology and Implant Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
| | - Yanqi Yang
- Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China
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10
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Chen Z, Deng XH, Jiang C, Wang JS, Li WP, Zhu KL, Li YH, Song B, Zhang ZZ. Repairing Avascular Meniscal Lesions by Recruiting Endogenous Targeted Cells Through Bispecific Synovial-Meniscal Aptamers. Am J Sports Med 2023; 51:1177-1193. [PMID: 36917829 DOI: 10.1177/03635465231159668] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
BACKGROUND Tissue engineering is a promising treatment option for meniscal lesions in the avascular area, but a favorable cell source and its utilization in tissue-engineered menisci remain uncertain. Therefore, a more controllable and convenient method for cell recruitment is required. HYPOTHESIS Circular bispecific synovial-meniscal (S-M) aptamers with a gelatin methacryloyl (GelMA) hydrogel can recruit endogenous synovial and meniscal cells to the site of the defect, thereby promoting in situ meniscal regeneration and chondroprotection. STUDY DESIGN Controlled laboratory study. METHODS Synovial and meniscal aptamers were filtered through systematic evolution of ligands by exponential enrichment (SELEX) and cross-linked to synthesize the S-M aptamer. A GelMA-aptamer system was constructed. An in vitro analysis of the bi-recruitment of synovial and meniscal cells was performed, and the migration and proliferation of the GelMA-aptamer hydrogel were also tested. For the in vivo assay, rabbits (n = 90) with meniscal defects in the avascular zone were divided into 3 groups: repair with the GelMA-aptamer hydrogel (GelMA-aptamer group), repair with the GelMA hydrogel (GelMA group), and no repair (blank group). Regeneration of the repaired meniscus and degeneration of the cartilage were assessed by gross and histological evaluations at 4, 8, and 12 weeks postoperatively. The mechanical properties of repaired menisci were also evaluated. RESULTS In vitro synovial and meniscal cells were recruited simultaneously by the S-M aptamer with high affiliation and specificity. The GelMA-aptamer hydrogel promoted the migration of targeted cells. Compared with the other groups, the GelMA-aptamer group showed enhanced fibrocartilaginous regeneration, lower cartilage degeneration, and better mechanical strength at 12 weeks after meniscal repair. CONCLUSION/CLINICAL RELEVANCE Bispecific S-M aptamers could be used for avascular meniscal repair by recruiting endogenous synovial and meniscal cells and promoting fibrocartilaginous regeneration.
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Affiliation(s)
- Zhong Chen
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xing-Hao Deng
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chuan Jiang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing-Song Wang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei-Ping Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ke-Long Zhu
- School of Chemistry, Sun Yat-sen University, Guangzhou, China
| | - Yu-Heng Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Song
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zheng-Zheng Zhang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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11
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Burns JS, Kassem M. Identifying Biomarkers for Osteogenic Potency Assay Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1420:39-58. [PMID: 37258783 DOI: 10.1007/978-3-031-30040-0_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
There has been extensive exploration of how cells may serve as advanced therapy medicinal products to treat skeletal pathologies. Osteoblast progenitors responsible for production of extracellular matrix that is subsequently mineralized during bone formation have been characterised as a rare bone marrow subpopulation of cell culture plastic adherent cells. Conveniently, they proliferate to form single-cell derived colonies of fibroblastoid cells, termed colony forming unit fibroblasts that can subsequently differentiate to aggregates resembling small areas of cartilage or bone. However, donor heterogeneity and loss of osteogenic differentiation capacity during extended cell culture have made the discovery of reliable potency assay biomarkers difficult. Nonetheless, functional osteoblast models derived from telomerised human bone marrow stromal cells have allowed extensive comparative analysis of gene expression, microRNA, morphological phenotypes and secreted proteins. This chapter highlights numerous insights into the molecular mechanisms underpinning osteogenic differentiation of multipotent stromal cells and bone formation, discussing aspects involved in the choice of useful biomarkers for functional attributes that can be quantitively measured in osteogenic potency assays.
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Affiliation(s)
- Jorge S Burns
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy.
| | - Moustapha Kassem
- University Hospital of Odense, University of Southern Denmark, Odense, Denmark
- Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
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12
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Sonoda S, Yamaza T. Extracellular vesicles rejuvenate the microenvironmental modulating function of recipient tissue-specific mesenchymal stem cells in osteopenia treatment. Front Endocrinol (Lausanne) 2023; 14:1151429. [PMID: 37033255 PMCID: PMC10073676 DOI: 10.3389/fendo.2023.1151429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Systemic transplantation of mesenchymal stem cells (MSCs), such as bone marrow MSCs (BMMSCs) and stem cells from human exfoliated deciduous teeth (SHED), is considered a prominent treatment for osteopenia. However, the mechanism of action of the transplanted MSCs has been poorly elucidated. In the recipient target tissue, including bone and bone marrow, only a few donor MSCs can be detected, suggesting that the direct contribution of donor MSCs may not be expected for osteopenia treatment. Meanwhile, secretomes, especially contents within extracellular vesicles (EVs) released from donor MSCs (MSC-EVs), play key roles in the treatment of several diseases. In this context, administrated donor MSC-EVs may affect bone-forming function of recipient cells. In this review, we discuss how MSC-EVs contribute to bone recovery recipient tissue in osteopenia. We also summarize a novel mechanism of action of systemic administration of SHED-derived EVs (SHED-EVs) in osteopenia. We found that reduced telomerase activity in recipient BMMSCs caused the deficiency of microenvironmental modulating function, including bone and bone marrow-like niche formation and immunomodulation in estrogen-deficient osteopenia model mice. Systemic administration of SHED-EVs could exert therapeutic effects on bone reduction via recovering the telomerase activity, leading to the rejuvenation of the microenvironmental modulating function in recipient BMMSCs, as seen in systemic transplantation of SHED. RNase-preconditioned donor SHED-EVs diminished the therapeutic benefits of administrated SHED-EVs in the recipient osteopenia model mice. These facts suggest that MSC-EV therapy targets the recipient BMMSCs to rejuvenate the microenvironmental modulating function via telomerase activity, recovering bone density. We then introduce future challenges to develop the reproducible MSC-EV therapy in osteopenia.
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13
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Fattahi R, Mohebichamkhorami F, Khani MM, Soleimani M, Hosseinzadeh S. Aspirin effect on bone remodeling and skeletal regeneration: Review article. Tissue Cell 2022; 76:101753. [PMID: 35180553 DOI: 10.1016/j.tice.2022.101753] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 01/21/2022] [Accepted: 02/06/2022] [Indexed: 12/21/2022]
Abstract
Bone tissues are one of the most complex tissues in the body that regenerate and repair themselves spontaneously under the right physiological conditions. Within the limitations of treating bone defects, mimicking tissue engineering through the recruitment of scaffolds, cell sources and growth factors, is strongly recommended. Aspirin is one of the non-steroidal anti-inflammatory drugs (NSAIDs) and has been used in clinical studies for many years due to its anti-coagulant effect. On the other hand, aspirin and other NSAIDs activate cytokines and some mediators in osteoclasts, osteoblasts and their progenitor cells in a defect area, thereby promoting bone regeneration. It also stimulates angiogenesis by increasing migration of endothelial cells and the newly developed vessels are of emergency in bone fracture repair. This review covers the role of aspirin in bone tissue engineering and also, highlights its chemical reactions, mechanisms, dosages, anti-microbial and angiogenesis activities.
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Affiliation(s)
- Roya Fattahi
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Mohebichamkhorami
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Khani
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Simzar Hosseinzadeh
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Gao X, Yu X, Zhang C, Wang Y, Sun Y, Sun H, Zhang H, Shi Y, He X. Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases. Stem Cell Rev Rep 2022; 18:2315-2327. [PMID: 35460064 PMCID: PMC9033418 DOI: 10.1007/s12015-022-10370-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2022] [Indexed: 02/06/2023]
Abstract
Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.
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Affiliation(s)
- Xingyu Gao
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Xiao Yu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Chang Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Yiming Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Yanan Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Hui Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Haiying Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Yingai Shi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China
| | - Xu He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, China.
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15
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Sonoda S, Yamaza T. A New Target of Dental Pulp-Derived Stem Cell-Based Therapy on Recipient Bone Marrow Niche in Systemic Lupus Erythematosus. Int J Mol Sci 2022; 23:ijms23073479. [PMID: 35408840 PMCID: PMC8998830 DOI: 10.3390/ijms23073479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/18/2022] [Accepted: 03/20/2022] [Indexed: 02/04/2023] Open
Abstract
Recent advances in mesenchymal stem/stromal cell (MSC) research have led us to consider the feasibility of MSC-based therapy for various diseases. Human dental pulp-derived MSCs (hDPSCs) have been identified in the dental pulp tissue of deciduous and permanent teeth, and they exhibit properties with self-renewal and in vitro multipotency. Interestingly, hDPSCs exhibit superior immunosuppressive functions toward immune cells, especially T lymphocytes, both in vitro and in vivo. Recently, hDPSCs have been shown to have potent immunomodulatory functions in treating systemic lupus erythematosus (SLE) in the SLE MRL/lpr mouse model. However, the mechanisms underlying the immunosuppressive efficacy of hDPSCs remain unknown. This review aims to introduce a new target of hDPSC-based therapy on the recipient niche function in SLE.
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16
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Teissier T, Temkin V, Pollak RD, Cox LS. Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes. Front Physiol 2022; 13:812157. [PMID: 35388291 PMCID: PMC8978545 DOI: 10.3389/fphys.2022.812157] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/27/2022] [Indexed: 01/10/2023] Open
Abstract
Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.
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Affiliation(s)
- Thibault Teissier
- Department of Biochemistry, University of Oxford, Oxford, United Kingdom
| | - Vladislav Temkin
- Division of Medicine, Department of Endocrinology and Metabolism, The Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rivka Dresner Pollak
- Division of Medicine, Department of Endocrinology and Metabolism, The Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Lynne S. Cox
- Department of Biochemistry, University of Oxford, Oxford, United Kingdom
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17
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Sonoda S, Murata S, Kato H, Zakaria F, Kyumoto-Nakamura Y, Uehara N, Yamaza H, Kukita T, Yamaza T. Targeting of Deciduous Tooth Pulp Stem Cell-Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus. THE JOURNAL OF IMMUNOLOGY 2021; 206:3053-3063. [PMID: 34078710 DOI: 10.4049/jimmunol.2001312] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/05/2021] [Indexed: 01/09/2023]
Abstract
Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)-like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV-administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.
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Affiliation(s)
- Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Sara Murata
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Fouad Zakaria
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Yukari Kyumoto-Nakamura
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Toshio Kukita
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, Fukuoka, Japan; and
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Quality by design to define critical process parameters for mesenchymal stem cell expansion. Biotechnol Adv 2021; 50:107765. [PMID: 33961977 DOI: 10.1016/j.biotechadv.2021.107765] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 05/01/2021] [Indexed: 12/15/2022]
Abstract
Stem cell-based therapeutic products could be the key to treat the deadliest current pathologies, ranging from neuro-degenerative to respiratory diseases. However, in order to bring these innovative therapeutics to a commercialization stage, reproducible manufacturing of high quality cell products is required. Although advances in cell culture techniques have led to more robust production processes and dramatically accelerated the development of early-phase clinical studies, challenges remain before regulatory approval, particularly to define and implement science-based quality standards (essential pre-requisites for national health agencies). In this regard, using new methodologies, such as Quality By Design (QBD), to build the production process around drug quality, could significantly reduce the chance of product rejection. This review-based work aims to perform a QBD approach to Mesenchymal Stem Cell (MSC) manufacturing in standard two-dimensional flasks, using published studies which have determined the impact of individual process parameters on defined Critical Quality Attributes (CQA). Along with this bibliographic analysis, parameter criticality was determined during the two main manufacturing stages (cell extraction and cell amplification) along with an overall classification in view of identifying the Critical Process Parameters (CPP). The analysis was performed in view of an improved standardization between research teams, and should contribute to reduce the gap towards compliant Good Manufacturing Practice (cGMP) manufacturing.
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19
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Mattei V, Martellucci S, Pulcini F, Santilli F, Sorice M, Delle Monache S. Regenerative Potential of DPSCs and Revascularization: Direct, Paracrine or Autocrine Effect? Stem Cell Rev Rep 2021; 17:1635-1646. [PMID: 33829353 PMCID: PMC8553678 DOI: 10.1007/s12015-021-10162-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
A new source of mesenchymal stem cells has recently been discovered, the so-called dental pulp derived stem cells (DPSCs) which therefore could represent potentially tools for regenerative medicine. DPSC originate from the neural crest and are physiologically involved in dentin homeostasis; moreover, they contribute to bone remodeling and differentiation into several tissues including cartilage, bone, adipose and nervous tissues. DPSCs have also been shown to influence the angiogenesis process, for example through the release of secretory factors or by differentiating into vascular and/or perivascular cells. Angiogenesis, that has a pivotal role in tissue regeneration and repair, is defined as the formation of new vessels from preexisting vessels and is mediated by mutual and reciprocal interactions between endothelial cells and perivascular cells. It is also known that co-cultures of perivascular and endothelial cells (ECs) can form a vascular network in vitro and also in vivo. Since DPSCs seem to have characteristics similar to pericytes, understanding the possible mechanism of interaction between DPSCs and ECs during neo-angiogenesis is dramatically important for the development of advanced clinical application in the field of regeneration.
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Affiliation(s)
- Vincenzo Mattei
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100, Rieti, Italy
- Department of Experimental Medicine, "Sapienza" University, 00161, Rome, Italy
| | - Stefano Martellucci
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100, Rieti, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Fanny Pulcini
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Francesca Santilli
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, 02100, Rieti, Italy
- Department of Experimental Medicine, "Sapienza" University, 00161, Rome, Italy
| | - Maurizio Sorice
- Department of Experimental Medicine, "Sapienza" University, 00161, Rome, Italy
| | - Simona Delle Monache
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy.
- StemTeCh Group, Chieti, Italy.
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20
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Atkinson SP. A preview of selected articles. Stem Cells 2021. [DOI: 10.1002/stem.3350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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21
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Carlone DL, Riba-Wolman RD, Deary LT, Tovaglieri A, Jiang L, Ambruzs DM, Mead BE, Shah MS, Lengner CJ, Jaenisch R, Breault DT. Telomerase expression marks transitional growth-associated skeletal progenitor/stem cells. Stem Cells 2021; 39:296-305. [PMID: 33438789 PMCID: PMC7986156 DOI: 10.1002/stem.3318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 11/20/2020] [Indexed: 12/28/2022]
Abstract
Skeletal progenitor/stem cells (SSCs) play a critical role in postnatal bone growth and maintenance. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in self‐renewing tissues. Here we investigated the role of mTert‐expressing cells in postnatal mouse long bone and found that mTert expression is enriched at the time of adolescent bone growth. mTert‐GFP+ cells were identified in regions known to house SSCs, including the metaphyseal stroma, growth plate, and the bone marrow. We also show that mTert‐expressing cells are a distinct SSC population with enriched colony‐forming capacity and contribute to multiple mesenchymal lineages, in vitro. In contrast, in vivo lineage‐tracing studies identified mTert+ cells as osteochondral progenitors and contribute to the bone‐forming cell pool during endochondral bone growth with a subset persisting into adulthood. Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance.
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Affiliation(s)
- Diana L Carlone
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
| | - Rebecca D Riba-Wolman
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Luke T Deary
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Alessio Tovaglieri
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Lijie Jiang
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Dana M Ambruzs
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Benjamin E Mead
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
| | - Manasvi S Shah
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher J Lengner
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - David T Breault
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
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22
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Razgonova MP, Zakharenko AM, Golokhvast KS, Thanasoula M, Sarandi E, Nikolouzakis K, Fragkiadaki P, Tsoukalas D, Spandidos DA, Tsatsakis A. Telomerase and telomeres in aging theory and chronographic aging theory (Review). Mol Med Rep 2020; 22:1679-1694. [PMID: 32705188 PMCID: PMC7411297 DOI: 10.3892/mmr.2020.11274] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/24/2020] [Indexed: 01/03/2023] Open
Abstract
The current review focuses on the connection of telomerase and telomeres with aging. In this review, we describe the changes in telomerase and telomere length (TEL) during development, their role in carcinogenesis processes, and the consequences of reduced telomerase activity. More specifically, the connection of TEL in peripheral blood cells with the development of aging‑associated diseases is discussed. The review provides systematic data on the role of telomerase in mitochondria, the biology of telomeres in stem cells, as well as the consequences of the forced expression of telomerase (telomerization) in human cells. Additionally, it presents the effects of chronic stress exposure on telomerase activity, the effect of TEL on fertility, and the effect of nutraceutical supplements on TEL. Finally, a comparative review of the chronographic theory of aging, presented by Olovnikov is provided based on currently available scientific research on telomere, telomerase activity, and the nature of aging by multicellular organisms.
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Affiliation(s)
- Mayya P. Razgonova
- N.I. Vavilov All-Russian Institute of Plant Genetic Resources, 190000 Saint-Petersburg, Russia
- Far Eastern Federal University, 690950 Vladivostok, Russia
| | - Alexander M. Zakharenko
- N.I. Vavilov All-Russian Institute of Plant Genetic Resources, 190000 Saint-Petersburg, Russia
- Far Eastern Federal University, 690950 Vladivostok, Russia
| | - Kirill S. Golokhvast
- N.I. Vavilov All-Russian Institute of Plant Genetic Resources, 190000 Saint-Petersburg, Russia
- Far Eastern Federal University, 690950 Vladivostok, Russia
- Pacific Geographical Institute, Far Eastern Branch of The Russian Academy of Sciences, 690041 Vladivostok, Russia
| | - Maria Thanasoula
- Metabolomic Μedicine, Health Clinics for Autoimmune and Chronic Diseases, 10674 Athens, Greece
| | - Evangelia Sarandi
- Metabolomic Μedicine, Health Clinics for Autoimmune and Chronic Diseases, 10674 Athens, Greece
| | | | - Persefoni Fragkiadaki
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
- Spin-Off Toxplus S.A., 71601 Heraklion, Greece
| | - Dimitris Tsoukalas
- Metabolomic Μedicine, Health Clinics for Autoimmune and Chronic Diseases, 10674 Athens, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion 71003, Greece
| | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
- Spin-Off Toxplus S.A., 71601 Heraklion, Greece
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23
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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24
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Cakouros D, Gronthos S. The changing epigenetic landscape of Mesenchymal Stem/Stromal Cells during aging. Bone 2020; 137:115440. [PMID: 32445894 DOI: 10.1016/j.bone.2020.115440] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/17/2020] [Accepted: 05/17/2020] [Indexed: 12/17/2022]
Abstract
There is mounting evidence in the literature that mesenchymal stromal/stem cell (MSC) like populations derived from different tissues, undergo epigenetic changes during aging, leading to compromised connective tissue integrity and function. This body of work has linked the biological aging of MSC to changes in their epigenetic signatures affecting growth, lifespan, self-renewal and multi-potential, due to deregulation of processes such as cellular senescence, oxidative stress, DNA damage, telomere shortening and DNA damage. This review addresses recent findings examining DNA methylation, histone modifications and miRNA changes in aging MSC populations. Moreover, we explore how epigenetic factors alter cellular pathways and associated biological networks, contributing to the MSC aging phenotype. Finally we discuss the crucial areas requiring a greater understanding of these processes, in order to piece together a global picture of the changing epigenetic landscape in MSC during aging.
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Affiliation(s)
- Dimitrios Cakouros
- Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
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25
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Sonoda S, Murata S, Nishida K, Kato H, Uehara N, Kyumoto YN, Yamaza H, Takahashi I, Kukita T, Yamaza T. Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model. Stem Cell Res Ther 2020; 11:296. [PMID: 32680564 PMCID: PMC7367365 DOI: 10.1186/s13287-020-01818-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/23/2020] [Accepted: 07/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) recovers bone loss in animal models of osteoporosis; however, the mechanisms underlying this remain unclear. Here, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) rescue osteoporotic phenotype. METHODS EVs were isolated from culture supernatant of SHED. SHED-EVs were treated with or without ribonuclease and systemically administrated into ovariectomized mice, followed by the function of recipient bone marrow mesenchymal stem cells (BMMSCs) including telomerase activity, osteoblast differentiation, and sepmaphorine-3A (SEMA3A) secretion. Subsequently, human BMMSCs were stimulated by SHED-EVs with or without ribonuclease treatment, and then human BMMSCs were examined regarding the function of telomerase activity, osteoblast differentiation, and SEMA3A secretion. Furthermore, SHED-EV-treated human BMMSCs were subcutaneously transplanted into the dorsal skin of immunocompromised mice with hydroxyapatite tricalcium phosphate (HA/TCP) careers and analyzed the de novo bone-forming ability. RESULTS We revealed that systemic SHED-EV-infusion recovered bone volume in ovariectomized mice and improved the function of recipient BMMSCs by rescuing the mRNA levels of Tert and telomerase activity, osteoblast differentiation, and SEMA3A secretion. Ribonuclease treatment depleted RNAs, including microRNAs, within SHED-EVs, and these RNA-depleted SHED-EVs attenuated SHED-EV-rescued function of recipient BMMSCs in the ovariectomized mice. These findings were supported by in vitro assays using human BMMSCs incubated with SHED-EVs. CONCLUSION Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating postmenopausal osteoporosis by targeting the telomerase activity of recipient BMMSCs.
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Affiliation(s)
- Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Sara Murata
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth & Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Kento Nishida
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroki Kato
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yukari N Kyumoto
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Division of Oral Health, Growth & Development, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan
| | - Ichiro Takahashi
- Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth & Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Toshio Kukita
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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26
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Zhang Q, Nettleship I, Schmelzer E, Gerlach J, Zhang X, Wang J, Liu C. Tissue Engineering and Regenerative Medicine Therapies for Cell Senescence in Bone and Cartilage. TISSUE ENGINEERING PART B-REVIEWS 2020; 26:64-78. [DOI: 10.1089/ten.teb.2019.0215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Qinghao Zhang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
- Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ian Nettleship
- Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eva Schmelzer
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jorg Gerlach
- Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xuewei Zhang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
| | - Jing Wang
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
| | - Changsheng Liu
- Department of Materials Science and Engineering, East China University of Science and Technology, Shanghai, P.R. China
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27
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Xie Y, Pan M, Gao Y, Zhang L, Ge W, Tang P. Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration. Cell Biosci 2019; 9:103. [PMID: 31890152 PMCID: PMC6929289 DOI: 10.1186/s13578-019-0369-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 12/20/2019] [Indexed: 01/10/2023] Open
Abstract
The failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (< 100 μg/mL), which is widely recommended for prevention of thrombosis, is very likely to be benefit for maintaining bone mass and qualities by activation of osteoblastic bone formation and inhibition of osteoclast activities via cyclooxygenase-independent manner. While, the roles of high-dose aspirin (150-300 μg/mL) and other NSAIDs in bone self-regeneration and fracture-healing process are difficult to elucidate owing to their dual effects on osteoclast activity and bone formation of osteoblast. In conclusion, this study highlighted the potential clinical applications of low-dose aspirin in abnormal bone remodeling as well as the risks of high-dose aspirin and other NSAIDs for relieving pain and anti-inflammation in fractures and orthopedic operations.
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Affiliation(s)
- Yong Xie
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
| | - Meng Pan
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Yanpan Gao
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Licheng Zhang
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
| | - Wei Ge
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Peifu Tang
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
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28
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Tao Z, Zhou W, Wu X, Lu H, Ma N, Li Y, Zhang R, Yang M, Xu HG. Local administration of aspirin improves osseointegration of hydroxyapatite-coated titanium implants in ovariectomized rats through activation of the Notch signaling pathway. J Biomater Appl 2019; 34:1009-1018. [PMID: 31757183 DOI: 10.1177/0885328219889630] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Zhoushan Tao
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Wanshu Zhou
- Department of Geriatrics, The Second Affiliated Hospital of Wannan Medical College, Anhui, People's Republic of China
| | - Xingjing Wu
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Hanli Lu
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Nengfeng Ma
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Yang Li
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Ruotian Zhang
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Min Yang
- Department of Trauma orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Anhui, People's Republic of China
| | - Hong-Guang Xu
- Department of Spine Surgery, Spine Research Center of Wannan Medical College, Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan hospital of Wannan Medical College, Anhui, People's Republic of China
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29
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Monocytes affect bone mineral density in pre- and postmenopausal women through ribonucleoprotein complex biogenesis by integrative bioinformatics analysis. Sci Rep 2019; 9:17290. [PMID: 31754224 PMCID: PMC6872746 DOI: 10.1038/s41598-019-53843-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 11/05/2019] [Indexed: 12/26/2022] Open
Abstract
Osteoporosis is one of the most common metabolic bone disease among pre- and postmenopausal women. As the precursors of osteoclast cells, circulating monocytes play important role in bone destruction and remodeling. The aim of study is to identify potential key genes and pathways correlated with the pathogenesis of osteoporosis. Then we construct novel estimation model closely linked to the bone mineral density (BMD) with key genes. Weighted gene co-expression network analysis (WGCNA) were conducted by collecting gene data set with 80 samples from gene expression omnibus (GEO) database. Besides, hub genes were identified by series of bioinformatics and machine learning algorithms containing protein-protein interaction (PPI) network, receiver operating characteristic curve and Pearson correlation. The direction of correlation coefficient were performed to screen for gene signatures with high BMD and low BMD. A novel BMD score system was put forward based on gene set variation analysis and logistic regression, which was validated by independent data sets. We identified six modules correlated with BMD. Finally 100 genes were identified as the high bone mineral density signatures while 130 genes were identified as low BMD signatures. Besides, we identified the significant pathway in monocytes: ribonucleoprotein complex biogenesis. What's more, our score validated it successfully.
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30
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Tao ZS, Wu XJ, Zhou WS, Wu XJ, Liao W, Yang M, Xu HG, Yang L. Local administration of aspirin with β-tricalcium phosphate/poly-lactic-co-glycolic acid (β-TCP/PLGA) could enhance osteoporotic bone regeneration. J Bone Miner Metab 2019; 37:1026-1035. [PMID: 31076895 DOI: 10.1007/s00774-019-01008-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
Composite materials β-tricalcium phosphate (β-TCP) and poly-lactic-co-glycolic acid (PLGA) have achieved stable bone regeneration without cell transplantation in previous studies. Recent research shows that aspirin (ASP) has great potential in promoting bone regeneration. The objective of the present study was to incorporate PLGA into β-TCP combined with a lower single-dose local administration of ASP to enhance its in vivo biodegradation and bone tissue growth. After the creation of a rodent critical-sized femoral metaphyseal bone defect, PLGA -modified β-TCP (TP) was prepared by mixing sieved granules of β-TCP and PLGA (50:50, v/v) for medical use, then TP with dripped 50 µg/0.1 ml and 100 µg/0.1 ml aspirin solution was implanted into the defect of OVX rats until death at 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, biomechanics and real time RT-PCR. The results of our study show that a single-dose local administration of ASP combined with the local usage of TP can increase the healing of defects in OVX rats. Single-dose local administration of aspirin can improve the transcription of genes involved in the regulation of bone formation and vascularization in the defect area, and inhibits osteoclast activity. Furthermore, treatments with a higher single-dose local administration of ASP and TP showed a stronger effect on accelerating the local bone formation than while using a lower dose of ASP. The results from our study demonstrate that the combination of a single-dose local administration of ASP and β-TCP/PLGA had an additive effect on local bone formation in osteoporosis rats, and bone regeneration by PLGA/β-TCP/ASP occured in a dose-dependent manner.
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Affiliation(s)
- Zhou-Shan Tao
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Xing-Jing Wu
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Wan-Shu Zhou
- Department of Geriatrics, The Second Affiliated Hospital of Wannan Medical College, No. 123, Kangfu Road, Wuhu, 241000, Anhui, People's Republic of China
| | - Xin-Ju Wu
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Wei Liao
- Department of Orthopedics, Children's Hospital of Nanjing Medical University, No. 8, Jiangdong South Road, Jianye District, Nanjing, People's Republic of China
| | - Min Yang
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China.
| | - Hong-Guang Xu
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China.
- Department of Spinal Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China.
| | - Lei Yang
- Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No. 109, Xueyuan West Road, Lucheng District, Wenzhou, 325000, Zhejiang, People's Republic of China
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31
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García-Sánchez D, Fernández D, Rodríguez-Rey JC, Pérez-Campo FM. Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells. World J Stem Cells 2019; 11:748-763. [PMID: 31692976 PMCID: PMC6828596 DOI: 10.4252/wjsc.v11.i10.748] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Darío Fernández
- Laboratorio de Biología Celular y Molecular, Facultad de Odontología, Universidad Nacional del Nordeste, Corrientes W3400, Argentina
| | - José C Rodríguez-Rey
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain.
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32
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Tanaka Y, Sonoda S, Yamaza H, Murata S, Nishida K, Kyumoto-Nakamura Y, Uehara N, Nonaka K, Kukita T, Yamaza T. Acetylsalicylic Acid Treatment and Suppressive Regulation of AKT Accelerate Odontogenic Differentiation of Stem Cells from the Apical Papilla. J Endod 2019; 45:591-598.e6. [DOI: 10.1016/j.joen.2019.01.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/07/2019] [Accepted: 01/17/2019] [Indexed: 01/26/2023]
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Cakouros D, Gronthos S. Epigenetic Regulation of Bone Marrow Stem Cell Aging: Revealing Epigenetic Signatures associated with Hematopoietic and Mesenchymal Stem Cell Aging. Aging Dis 2019; 10:174-189. [PMID: 30705777 PMCID: PMC6345334 DOI: 10.14336/ad.2017.1213] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 12/13/2017] [Indexed: 12/18/2022] Open
Abstract
In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. We summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. With the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. We begin by briefly discussing the initial observations in yeast, drosophila and Caenorhabditis elegans (C. elegans) that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. We then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of DNA methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. Given the reversible nature of epigenetic modifications we envisage “epi” targeted therapy as a means to reprogram aged stem cells into their younger counterparts.
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Affiliation(s)
- Dimitrios Cakouros
- 1Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.,2South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Stan Gronthos
- 1Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.,2South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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Yang YHK. Aging of mesenchymal stem cells: Implication in regenerative medicine. Regen Ther 2018; 9:120-122. [PMID: 30525083 PMCID: PMC6222976 DOI: 10.1016/j.reth.2018.09.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 08/30/2018] [Accepted: 09/13/2018] [Indexed: 12/15/2022] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) represent a great candidate for various clinical applications including regenerative medicine. However, aging both in vivo and in vitro can significantly compromise MSC characteristics and performance. This paper highlights current thoughts on senescence-induced damage to MSCs that should be considered prior to their use for regeneration of different cells, tissues or organs.
Multipotent mesenchymal stem cells give rise to different cell lineages of mesodermal origin. Mesenchymal stem cells can undergo aging process during extensive in-vitro expansion. Senescence, both in vivo and in vitro, damages the regenerative and therapeutic potential of mesenchymal stem cells.
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Affiliation(s)
- Yueh-Hsun Kevin Yang
- Grove School of Engineering, The City University of New York - the City College, New York, NY 10031, USA
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Vlăsceanu GM, Amărandi RM, Ioniță M, Tite T, Iovu H, Pilan L, Burns JS. Versatile graphene biosensors for enhancing human cell therapy. Biosens Bioelectron 2018; 117:283-302. [DOI: 10.1016/j.bios.2018.04.053] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/18/2018] [Accepted: 04/25/2018] [Indexed: 01/04/2023]
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Liu D, Kou X, Chen C, Liu S, Liu Y, Yu W, Yu T, Yang R, Wang R, Zhou Y, Shi S. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res 2018; 28:918-933. [PMID: 30030518 PMCID: PMC6123409 DOI: 10.1038/s41422-018-0070-2] [Citation(s) in RCA: 212] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 04/26/2018] [Accepted: 07/02/2018] [Indexed: 12/19/2022] Open
Abstract
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3-/- mice to show that reduction of apoptotic body formation significantly impaired the self-renewal and osteo-/adipo-genic differentiation of bone marrow mesenchymal stem cells (MSCs). Systemic infusion of exogenous apoptotic bodies rescued the MSC impairment and also ameliorated the osteopenia phenotype in MRL/lpr, Caspase 3-/- and ovariectomized (OVX) mice. Mechanistically, we showed that MSCs were able to engulf apoptotic bodies via integrin αvβ3 and reuse apoptotic body-derived ubiquitin ligase RNF146 and miR-328-3p to inhibit Axin1 and thereby activate the Wnt/β-catenin pathway. Moreover, we used a parabiosis mouse model to reveal that apoptotic bodies participated in the circulation to regulate distant MSCs. This study identifies a previously unknown role of apoptotic bodies in maintaining MSC and bone homeostasis in both physiological and pathological contexts and implies the potential use of apoptotic bodies to treat osteoporosis.
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Affiliation(s)
- Dawei Liu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA
| | - Xiaoxing Kou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Shiyu Liu
- School of Stomatology, Fourth Military Medical University, Xi'an, Shanxi, 710032, China
| | - Yao Liu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Wenjing Yu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Tingting Yu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Ruili Yang
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Runci Wang
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA.
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA, 90033, USA.
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Current Strategies to Generate Human Mesenchymal Stem Cells In Vitro. Stem Cells Int 2018; 2018:6726185. [PMID: 30224922 PMCID: PMC6129345 DOI: 10.1155/2018/6726185] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 07/31/2018] [Accepted: 08/09/2018] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are heterogeneous multipotent stem cells that are involved in the development of mesenchyme-derived evolving structures and organs during ontogeny. In the adult organism, reservoirs of MSCs can be found in almost all tissues where MSCs contribute to the maintenance of organ integrity. The use of these different MSCs for cell-based therapies has been extensively studied over the past years, which highlights the use of MSCs as a promising option for the treatment of various diseases including autoimmune and cardiovascular disorders. However, the proportion of MSCs contained in primary isolates of adult tissue biopsies is rather low and, thus, vigorous ex vivo expansion is needed especially for therapies that may require extensive and repetitive cell substitution. Therefore, more easily and accessible sources of MSCs are needed. This review summarizes the current knowledge of the different strategies to generate human MSCs in vitro as an alternative method for their applications in regenerative therapy.
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Abstract
Mesenchymal stem cells (MSCs) have been discovered in almost every organ and tissue. MSCs are a heterogeneous population of cells with the capacity to self-renew and show multilineage differentiation. MSCs possess immunomodulatory properties by regulating multiple types of immune cells. They are emerging as a promising therapeutic agent, and have been widely used for cell-based tissue regeneration and immune therapies. A further understanding of the biological characteristics of MSCs is a prerequisite to develop more efficient MSC-based therapies. This article reviews the current understanding of different MSC populations in orofacial tissue compared with those derived from bone marrow.
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Affiliation(s)
- Xueli Mao
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Affiliated Stomatological Hospital, Sun Yat-sen University, 55 West Lingyuan Rd, Yuexiu District, Guangzhou 510055, China
| | - Yao Liu
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatric Dentistry, School of Stomatology, China Medical University, 117 South Nanjing Street, Heping District, Shenyang 110002, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Songtao Shi
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Yuan M, Zhan Y, Hu W, Li Y, Xie X, Miao N, Jin H, Zhang B. Aspirin promotes osteogenic differentiation of human dental pulp stem cells. Int J Mol Med 2018; 42:1967-1976. [PMID: 30085338 PMCID: PMC6108875 DOI: 10.3892/ijmm.2018.3801] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/30/2018] [Indexed: 12/19/2022] Open
Abstract
Human dental pulp stem cells (hDPSCs) possess self‑renewal and osteogenic differentiation properties, and have been used for orofacial bone regeneration and periodontal treatment. Aspirin has been demonstrated to enhance the regeneration of bone marrow mesenchymal stem cells (MSCs); however, the impact of aspirin on the osteogenic differentiation of hDPSCs remains unknown. In the present study, hDPSCs were characterized by flow cytometry, while their clonogenic potential and multipotency were assessed using alizarin red, Oil red O and alcian blue staining. The effect of aspirin on hDPSC viability was assessed using Cell Counting Kit‑8 assay. Osteogenic capacity was examined by alkaline phosphatase activity, alizarin red staining, reverse transcription‑polymerase chain reaction and western blotting. Furthermore, in vivo cranial defects were established in Sprague‑Dawley rats to evaluate the effect of aspirin on hDPSC‑based bone regeneration. Anorganic bovine bone was used as a bone replacement material and as the carrier for hDPSCs. New bone formation was observed through radiographic and histological analysis. The study demonstrated that hDPSCs expressed MSC markers and possessed multipotency in vitro. Aspirin was non‑toxic to hDPSCs at a concentration of ≤100 µg/ml and enhanced the osteogenesis of hDPSCs in vitro. Aspirin significantly increased hDPSC‑based bone formation in the rat cranial defect model at 8 or 12 weeks post‑implantation (P<0.05). The data suggested that aspirin promotes the osteogenic potential of hDPSCs in vitro and in vivo. Overall, the present study indicated that aspirin improves the bone regeneration capacity of hDPSCs.
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Affiliation(s)
- Mengtong Yuan
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yuanbo Zhan
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Weiping Hu
- Department of Prosthodontics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ying Li
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xiaohua Xie
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Nan Miao
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Han Jin
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Bin Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Yang R, Liu Y, Yu T, Liu D, Shi S, Zhou Y, Zhou Y. Hydrogen sulfide maintains dental pulp stem cell function via TRPV1-mediated calcium influx. Cell Death Discov 2018; 4:1. [PMID: 30062050 PMCID: PMC6060166 DOI: 10.1038/s41420-018-0071-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 02/17/2018] [Accepted: 02/20/2018] [Indexed: 12/21/2022] Open
Abstract
Hydrogen sulfide (H2S), an endogenous gasotransmitter, mediated a variety of biological processes through multiple signaling pathways, and aberrant H2S metabolism has been associated with mesenchymal stem cell (MSC) dysfunction. Here we employed the small interfering RNA treatment for cystathionine β-synthase (CBS), cystathionine γ-lyase, the main enzymes to synthesize H2S, and CBS-knockout mice to analyze the effect of H2S on dental pulp homeostasis. We showed that H2S deficiency attenuated dental pulp stem cell (DPSC) osteogenic/dentinogenic differentiation in vitro and in vivo with enhanced cell proliferation. Mechanically, H2S facilitated the transient receptor potential action channel subfamily V member 1-mediated calcium (Ca2+) influx, which subsequently activated the β-catenin pathway. While H2S deficiency decreased Ca2+, resulting in glycogen synthase kinase-3β-mediated β-catenin degradation, which controls proliferation and differentiation of DPSCs. Consistently, H2S-deficient mice displayed disturbed pattern of dental pulp and less dentin formation. In this study, we identified a previously unknown mechanism by which H2S regulates DPSC lineage determination and dental pulp homeostasis.
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Affiliation(s)
- Ruili Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 100081 Beijing, China
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, 100050 Beijing, China
| | - Tingting Yu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 100081 Beijing, China
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Dawei Liu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 100081 Beijing, China
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Songtao Shi
- Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Yongsheng Zhou
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 100081 Beijing, China
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, 100081 Beijing, China
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Yang R, Yu T, Kou X, Gao X, Chen C, Liu D, Zhou Y, Shi S. Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter. Nat Commun 2018; 9:2143. [PMID: 29858571 PMCID: PMC5984622 DOI: 10.1038/s41467-018-04464-6] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 05/02/2018] [Indexed: 12/13/2022] Open
Abstract
Ten-eleven translocation (Tet) family-mediated DNA oxidation represents an epigenetic modification capable of converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which regulates various biological processes. However, it is unknown whether Tet family affects mesenchymal stem cells (MSCs) or the skeletal system. Here we show that depletion of Tet1 and Tet2 results in impaired self-renewal and differentiation of bone marrow MSCs (BMMSCs) and a significant osteopenia phenotype. Tet1 and Tet2 deficiency reduces demethylation of the P2rX7 promoter and downregulates exosome release, leading to intracellular accumulation of miR-297a-5p, miR-297b-5p, and miR-297c-5p. These miRNAs inhibit Runx2 signaling to impair BMMSC function. We show that overexpression of P2rX7 rescues the impaired BMMSCs and osteoporotic phenotype in Tet1 and Tet2 double knockout mice. These results indicate that Tet1 and Tet2 play a critical role in maintaining BMMSC and bone homeostasis through demethylation of P2rX7 to control exosome and miRNA release. This Tet/P2rX7/Runx2 cascade may serve as a target for the development of novel therapies for osteopenia disorders.
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Affiliation(s)
- Ruili Yang
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
- Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China
| | - Tingting Yu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Xiaoxing Kou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Xiang Gao
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
- College of Stomatology and Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 401147, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Dawei Liu
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China.
- Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China.
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA.
- Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China.
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Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro. Stem Cell Res Ther 2018; 9:131. [PMID: 29751774 PMCID: PMC5948736 DOI: 10.1186/s13287-018-0876-3] [Citation(s) in RCA: 407] [Impact Index Per Article: 58.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/11/2018] [Accepted: 04/13/2018] [Indexed: 12/15/2022] Open
Abstract
Background Adult mesenchymal stem cells (MSCs) hold great promise for regenerative medicine because of their self-renewal, multipotency, and trophic and immunosuppressive effects. Due to the rareness and high heterogeneity of freshly isolated MSCs, extensive in-vitro passage is required to expand their populations prior to clinical use; however, senescence usually accompanies and can potentially affect MSC characteristics and functionality. Therefore, a thorough characterization of the variations in phenotype and differentiation potential of in-vitro aging MSCs must be sought. Methods Human bone marrow-derived MSCs were passaged in vitro and cultivated with either DMEM-based or αMEM-based expansion media. Cells were prepared for subculture every 10 days up to passage 8 and were analyzed for cell morphology, proliferative capacity, and surface marker expression at the end of each passage. The gene expression profile and adipogenic and osteogenic differentiation capability of MSCs at early (passage 4) and late (passage 8) passages were also evaluated. Results In-vitro aging MSCs gradually lost the typical fibroblast-like spindle shape, leading to elevated morphological abnormality and inhomogeneity. While the DMEM-based expansion medium better facilitated MSC proliferation in the early passages, the cell population doubling rate reduced over time in both DMEM and αMEM groups. CD146 expression decreased with increasing passage number only when MSCs were cultured under the DMEM-based condition. Senescence also resulted in MSCs with genetic instability, which was further regulated by the medium recipe. Regardless of the expansion condition, MSCs at both passages 4 and 8 could differentiate into adipocyte-like cells whereas osteogenesis of aged MSCs was significantly compromised. For osteogenic induction, use of the αMEM-based expansion medium yielded longer osteogenesis and better quality. Conclusions Human MSCs subjected to extensive in-vitro passage can undergo morphological, phenotypic, and genetic changes. These properties are also modulated by the medium composition employed to expand the cell populations. In addition, adipogenic potential may be better preserved over osteogenesis in aged MSCs, suggesting that MSCs at early passages must be used for osteogenic differentiation. The current study presents valuable information for future basic science research and clinical applications leading to the development of novel MSC-based therapeutic strategies for different diseases. Electronic supplementary material The online version of this article (10.1186/s13287-018-0876-3) contains supplementary material, which is available to authorized users.
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Yang S, Guo L, Su Y, Wen J, Du J, Li X, Liu Y, Feng J, Xie Y, Bai Y, Wang H, Liu Y. Nitric oxide balances osteoblast and adipocyte lineage differentiation via the JNK/MAPK signaling pathway in periodontal ligament stem cells. Stem Cell Res Ther 2018; 9:118. [PMID: 29716662 PMCID: PMC5930947 DOI: 10.1186/s13287-018-0869-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/28/2018] [Accepted: 04/12/2018] [Indexed: 12/21/2022] Open
Abstract
Background Critical tissues that undergo regeneration in periodontal tissue are of mesenchymal origin; thus, investigating the regulatory mechanisms underlying the fate of periodontal ligament stem cells could be beneficial for application in periodontal tissue regeneration. Nitric oxide (NO) regulates many biological processes in developing embryos and adult stem cells. The present study was designed to investigate the effects of NO on the function of human periodontal ligament stem cells (PDLSCs) as well as to elucidate the underlying molecular mechanisms. Methods Immunofluorescent staining and flow cytometry were used for stem cell identification. Western blot, reverse transcription polymerase chain reaction (RT-PCR), immunofluorescent staining, and flow cytometry were used to examine the expression of NO-synthesizing enzymes. The proliferative capacity of PDLSCs was determined by EdU assays. The osteogenic potential of PDLSCs was tested using alkaline phosphatase (ALP) staining, Alizarin Red staining, and calcium concentration detection. Oil Red O staining was used to analyze the adipogenic ability. Western blot, RT-PCR, and staining were used to examine the signaling pathway. Results Human PDLSCs expressed both inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) and produced NO. Blocking the generation of NO with the NOS inhibitor l-NG-monomethyl arginine (l-NMMA) had no influence on PDLSC proliferation and apoptosis but significantly attenuated the osteogenic differentiation capacity and stimulated the adipogenic differentiation capacity of PDLSCs. Increasing the physiological level of NO with NO donor sodium nitroprusside (SNP) significantly promoted the osteogenic differentiation capacity but reduced the adipogenic differentiation capacity of PDLSCs. NO balances the osteoblast and adipocyte lineage differentiation in periodontal ligament stem cells via the c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions NO is essential for maintaining the balance between osteoblasts and adipocytes in PDLSCs via the JNK/MAPK signaling pathway. Graphical Abstract NO balances osteoblast and adipocyte lineage differentiation via JNK/MAPK signaling pathway![]() Electronic supplementary material The online version of this article (10.1186/s13287-018-0869-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shan Yang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Lijia Guo
- Department of Orthodontics, Capital Medical University School of Stomatology, Beijing, People's Republic of China
| | - Yingying Su
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Jing Wen
- Department of Orthodontics, Capital Medical University School of Stomatology, Beijing, People's Republic of China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Xiaoyan Li
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yitong Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Jie Feng
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yongmei Xie
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yuxing Bai
- Department of Orthodontics, Capital Medical University School of Stomatology, Beijing, People's Republic of China
| | - Hao Wang
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
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Potential of iPSC-Derived Mesenchymal Stromal Cells for Treating Periodontal Disease. Stem Cells Int 2018; 2018:2601945. [PMID: 29731776 PMCID: PMC5872653 DOI: 10.1155/2018/2601945] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/31/2018] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal cell-like populations have been derived from mouse-induced pluripotent stem cells (miPSC-MSC) with the capability for tissue regeneration. In this study, murine iPSC underwent differentiation towards an MSC-like immunophenotype. Stable miPSC-MSC cultures expressed the MSC-associated markers, CD73, CD105, and Sca-1, but lacked expression of the pluripotency marker, SSEA1, and hematopoietic markers, CD34 and CD45. Functionally, miPSC-MSC exhibited the potential for trilineage differentiation into osteoblasts, adipocytes, and chondrocytes and the capacity to suppress the proliferation of mitogen-activated splenocytes. The efficacy of miPSC-MSC was assessed in an acute inflammation model following systemic or local delivery into mice with subcutaneous implants containing heat-inactivated P. gingivalis. Histological analysis revealed less inflammatory cellular infiltrate within the sponges in mice treated with miPSC-MSC cells delivered locally rather than systemically. Assessment of proinflammatory cytokines in mouse spleens found that CXCL1 transcripts and protein were reduced in mice treated with miPSC-MSC. In a periodontitis model, mice subjected to oral inoculation with P. gingivalis revealed less bone tissue destruction and inflammation within the jaws when treated with miPSC-MSC compared to PBS alone. Our results demonstrated that miPSC-MSC derived from iPSC have the capacity to control acute and chronic inflammatory responses associated with the destruction of periodontal tissue. Therefore, miPSC-MSC present a promising novel source of stromal cells which could be used in the treatment of periodontal disease and other inflammatory systemic diseases such as rheumatoid arthritis.
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Kou X, Xu X, Chen C, Sanmillan ML, Cai T, Zhou Y, Giraudo C, Le A, Shi S. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci Transl Med 2018; 10:eaai8524. [PMID: 29540618 PMCID: PMC6310133 DOI: 10.1126/scitranslmed.aai8524] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 03/06/2017] [Accepted: 02/13/2018] [Indexed: 12/16/2022]
Abstract
Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase-1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor-α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor κB pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing.
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Affiliation(s)
- Xiaoxing Kou
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA
- Department of Orthodontics, Peking University School and Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China
| | - Xingtian Xu
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA
| | - Maria Laura Sanmillan
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tao Cai
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20982, USA
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China
| | - Claudio Giraudo
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anh Le
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
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Krajewska-Włodarczyk M, Owczarczyk-Saczonek A, Placek W, Osowski A, Wojtkiewicz J. Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy. Int J Mol Sci 2018; 19:E623. [PMID: 29470431 PMCID: PMC5855845 DOI: 10.3390/ijms19020623] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 02/11/2018] [Accepted: 02/16/2018] [Indexed: 12/13/2022] Open
Abstract
Changes in articular cartilage during the aging process are a stage of natural changes in the human body. Old age is the major risk factor for osteoarthritis but the disease does not have to be an inevitable consequence of aging. Chondrocytes are particularly prone to developing age-related changes. Changes in articular cartilage that take place in the course of aging include the acquisition of the senescence-associated secretory phenotype by chondrocytes, a decrease in the sensitivity of chondrocytes to growth factors, a destructive effect of chronic production of reactive oxygen species and the accumulation of the glycation end products. All of these factors affect the mechanical properties of articular cartilage. A better understanding of the underlying mechanisms in the process of articular cartilage aging may help to create new therapies aimed at slowing or inhibiting age-related modifications of articular cartilage. This paper presents the causes and consequences of cellular aging of chondrocytes and the biological therapeutic outlook for the regeneration of age-related changes of articular cartilage.
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Affiliation(s)
- Magdalena Krajewska-Włodarczyk
- Department of Rheumatology, Municipal Hospital in Olsztyn, 10-900 Olsztyn, Poland.
- Department of Internal Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Adam Osowski
- Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
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PD-1 is required to maintain stem cell properties in human dental pulp stem cells. Cell Death Differ 2018; 25:1350-1360. [PMID: 29472716 DOI: 10.1038/s41418-018-0077-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 01/19/2018] [Accepted: 01/26/2018] [Indexed: 01/09/2023] Open
Abstract
Programmed cell death-1 (PD-1) belongs to an inhibitory signaling pathway capable of maintaining central and peripheral immune tolerance. Blockage of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases. However, it is unknown whether PD-1 pathway regulates stem cell function. It is generally believed that mesenchymal stem cells (MSCs) produce PD-1 ligand, but fail to express PD-1. In this study, we show that neural crest-derived MSCs from dental pulp (MSC-DP), but not MSCs from bone marrow, expressed PD-1. Knocking down PD-1 expression in MSC-DP results in a significantly reduced capacity for cell proliferation and accelerated multipotential differentiation. Mechanistically, we show that PD-1 regulates a SHP2/ERK/Notch cascade to maintain proliferation and a SHP2/ERK/β-catenin cascade to inhibit osteo-/odontogenic differentiation. This study indicates that PD-1 is a key surface molecule controlling cell proliferation and multipotential differentiation of MSC-DP. Through regulating PD-1/SHP2/ERK signaling, we can significantly improve the quality and quantity of culture-expanded MSC-DP for potential clinical therapies.
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Xia Y, Chen H, Zhang F, Wang L, Chen B, Reynolds MA, Ma J, Schneider A, Gu N, Xu HHK. Injectable calcium phosphate scaffold with iron oxide nanoparticles to enhance osteogenesis via dental pulp stem cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:423-433. [PMID: 29355052 DOI: 10.1080/21691401.2018.1428813] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Literature search revealed no systematic report on iron oxide nanoparticle-incorporating calcium phosphate cement scaffolds (IONP-CPC). The objectives of this study were to: (1) use γFe2O3 nanoparticles (γIONPs) and αFe2O3 nanoparticles (αIONPs) to develop novel IONP-CPC scaffolds, and (2) investigate human dental pulp stem cells (hDPSCs) seeding on IONP-CPC for bone tissue engineering for the first time. IONP-CPC scaffolds were fabricated. Physiochemical properties of IONP-CPC scaffolds were characterized. hDPSC seeding on scaffolds, cell proliferation, osteogenic differentiation and bone matrix mineral synthesis by cells were measured. Our data demonstrated that the osteogenic differentiation of hDPSCs was markedly enhanced via IONP incorporation into CPC. Substantial increases (about three folds) in ALP activity and osteogenic gene expressions were achieved over those without IONPs. Bone matrix mineral synthesis by the cells was increased by two- to three folds over that without IONPs. The enhanced cellular osteogenesis was attributed to: (1) the surface nanotopography of IONP-CPC scaffold, and (2) the cell internalization of IONPs released from IONP-CPC scaffold. Our results demonstrate that the novel CPC functionalized with IONPs is promising to promote osteoinduction and bone regeneration. In conclusion, it is highly promising to incorporate γIONPs and αIONPs into CPC scaffold for bone tissue engineering, yielding substantially better stem cell attachment, spreading and osteogenic differentiation, and much greater bone mineral synthesis by the seeded cells. Therefore, novel CPC scaffolds containing γIONPs and αIONPs are promising for dental, craniofacial and orthopaedic applications to substantially enhance bone regeneration.
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Affiliation(s)
- Yang Xia
- a Jiangsu Key Laboratory of Oral Diseases , Nanjing Medical University , Nanjing , China.,b Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering , Southeast University , Nanjing , China.,c Department of Advanced Oral Sciences and Therapeutics , University of Maryland School of Dentistry , Baltimore , MD , USA
| | - Huimin Chen
- a Jiangsu Key Laboratory of Oral Diseases , Nanjing Medical University , Nanjing , China
| | - Feimin Zhang
- a Jiangsu Key Laboratory of Oral Diseases , Nanjing Medical University , Nanjing , China.,d Collaborative Innovation Center of Suzhou Nano Science and Technology , Suzhou , China
| | - Lin Wang
- c Department of Advanced Oral Sciences and Therapeutics , University of Maryland School of Dentistry , Baltimore , MD , USA.,e VIP Integrated Department, School and Hospital of Stomatology , Jilin University , Changchun , China
| | - Bo Chen
- b Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering , Southeast University , Nanjing , China
| | - Mark A Reynolds
- c Department of Advanced Oral Sciences and Therapeutics , University of Maryland School of Dentistry , Baltimore , MD , USA
| | - Junqing Ma
- a Jiangsu Key Laboratory of Oral Diseases , Nanjing Medical University , Nanjing , China
| | - Abraham Schneider
- f Department of Oncology and Diagnostic Sciences , University of Maryland School of Dentistry , Baltimore , MD , USA
| | - Ning Gu
- b Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering , Southeast University , Nanjing , China.,d Collaborative Innovation Center of Suzhou Nano Science and Technology , Suzhou , China
| | - Hockin H K Xu
- c Department of Advanced Oral Sciences and Therapeutics , University of Maryland School of Dentistry , Baltimore , MD , USA.,g Center for Stem Cell Biology and Regenerative Medicine , University of Maryland School of Medicine , Baltimore , MD , USA.,h University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore , MD , USA
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Kim Y, Zhang Z, Shim JH, Lee TS, Tung CH. A cell surface clicked navigation system to direct specific bone targeting. Bioorg Med Chem 2017; 26:758-764. [PMID: 29306547 DOI: 10.1016/j.bmc.2017.12.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/22/2017] [Accepted: 12/24/2017] [Indexed: 11/26/2022]
Abstract
Cell therapies are promising up-and-coming therapeutic strategies for many diseases. For maximal therapeutic benefits, injected cells have to navigate their way to a designated area, including organ and tissue; unfortunately, the majority of therapeutic cells are currently administered without a guide or homing device. To improve this serious shortcoming, a functionalization method was developed to equip cells with a homing signal. Its application was demonstrated by applying an Azadibenzocyclooctyne-bisphosphonate (ADIBO-BP) and azide paired bioorthogonal chemistry on cells for bone specific homing. Jurkat T cells and bone marrow derived stromal cells (BMSCs) were cultured with tetraacetylated N-azidoacetyl-d-mannosamine (Ac4ManNAz) to place unnatural azido groups onto the cell's surface; these azido groups were then reacted with ADIBO-BP. The tethered bisphosphonates were able to bring Jurkat cells to hydroxyapatite, the major component of bone, and mineralized SAOS-2 cells. The incorporated BP groups also enhanced the specific affinity of BMSCs to mouse femur bone fragments in vitro. The introduced navigation strategy is expected to have a broad application in cell therapy, because through the biocompatible ADIBO and azide reactive pair, various homing signals could be efficiently anchored onto therapeutic cells.
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Affiliation(s)
- Young Kim
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA
| | - Zhe Zhang
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA
| | - Jae-Hyuck Shim
- Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Tae Sup Lee
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA
| | - Ching-Hsuan Tung
- Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, 413 East 69th Street, New York, NY 10021, USA.
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50
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Lee EJ, Hwang I, Lee JY, Park JN, Kim KC, Kim GH, Kang CM, Kim I, Lee SY, Kim HS. Hepatocyte Growth Factor Improves the Therapeutic Efficacy of Human Bone Marrow Mesenchymal Stem Cells via RAD51. Mol Ther 2017; 26:845-859. [PMID: 29398486 DOI: 10.1016/j.ymthe.2017.12.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 11/29/2017] [Accepted: 12/14/2017] [Indexed: 02/08/2023] Open
Abstract
Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease.
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Affiliation(s)
- Eun Ju Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Injoo Hwang
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ji Yeon Lee
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jong Nam Park
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Keun Cheon Kim
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Gi-Hwan Kim
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Chang-Mo Kang
- Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Irene Kim
- Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seo-Yeon Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyo-Soo Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
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