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Sugai Y, Hamai R, Shiwaku Y, Anada T, Tsuchiya K, Kimura T, Tadano M, Yamauchi K, Takahashi T, Egusa H, Suzuki O. Effect of Octacalcium Phosphate on Osteogenic Differentiation of Induced Pluripotent Stem Cells in a 3D Hybrid Spheroid Culture. Biomimetics (Basel) 2025; 10:205. [PMID: 40277604 PMCID: PMC12025270 DOI: 10.3390/biomimetics10040205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/14/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Octacalcium phosphate (OCP) has been shown to exhibit an osteogenic property and, therefore, has been utilized recently as a bone substitute, clinically. However, the stimulatory capacity for induced pluripotent stem (iPS) cells is not known. This study investigated whether OCP enhances osteoblastic differentiation of three-dimensionally cultured spheroids of iPS cells compared to hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP). Mouse iPS cells were mixed with smaller (less than 53 μm) or larger (300-500 μm) sizes of calcium phosphate (CaP) granules and cultured in a laboratory-developed oxygen-permeable culture chip under minimizing hypoxia for up to 21 days. Osteoblastic differentiation was estimated by the cellular alkaline phosphatase (ALP) activities. The degree of supersaturation (DS) with respect to CaP phases was determined from the media chemical compositions. Incubated CaP materials were characterized by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The culture promoted well the formation of hybrid spheroids of CaP materials and iPS cells regardless of the type of materials and their granule sizes. The ALP activity of OCP was about 1.5 times higher than that of β-TCP and HA in smaller granule sizes. FTIR, XRD, and DS analyses showed that larger OCP granules tended to hydrolyze to HA slightly faster than smaller granules with time while HA and β-TCP materials tended to remain unchanged. In conclusion, the results suggest that OCP enhances the osteogenic differentiation of iPS cells more than HA and β-TCP through a mechanism of hydrolyzing to HA. This inherent material property of OCP is essential for enhancing the osteoblastic differentiation of iPS cells.
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Affiliation(s)
- Yuki Sugai
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
- Division of Oral and Maxillofacial Reconstructive Surgery, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Ryo Hamai
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Yukari Shiwaku
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Takahisa Anada
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
- Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka 816-8580, Japan
| | - Kaori Tsuchiya
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Tai Kimura
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
- Division of Oral and Maxillofacial Reconstructive Surgery, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Manami Tadano
- Division of Pediatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Kensuke Yamauchi
- Division of Oral and Maxillofacial Reconstructive Surgery, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Tetsu Takahashi
- Division of Oral and Maxillofacial Reconstructive Surgery, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
| | - Osamu Suzuki
- Division of Craniofacial Function Engineering (Division of Biomaterials Science and Engineering), Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
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Yanli Z, Jiayao M, Chunqing Z, Yuting Z, Zhiyan Z, Yulin Z, Minghan L, Longquan S, Dehong Y, Wenjuan Y. MY-1-Loaded Nano-Hydroxyapatite Accelerated Bone Regeneration by Increasing Type III Collagen Deposition in Early-Stage ECM via a Hsp47-Dependent Mechanism. Adv Healthc Mater 2023; 12:e2300332. [PMID: 36999955 DOI: 10.1002/adhm.202300332] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/13/2023] [Indexed: 04/01/2023]
Abstract
The extracellular matrix (ECM) plays a crucial part in regulating stem cell function through its distinctive mechanical and chemical effect. Therefore, it is worth studying how to activate the driving force of osteoblast cells by dynamic changing of ECM and accelerate the bone regeneration. In this research, a novel peptide MY-1 is designed and synthesized. To achieve its sustained releasing, the nano-hydroxyapatite (nHA) is chosen as the carrier of MY-1 by mixed adsorption. The results reveal that the sustainable releasing of MY-1 regulates the synthesis and secretion of ECM from rat bone marrow mesenchymal stem cells (rBMSCs), which promotes the cell migration and osteogenic differentiation in the early stage of bone regeneration. Further analyses demonstrate that MY-1 increases the expression and nuclear translocation of β-catenin, and then upregulates the level of heat shock protein 47 (Hsp47), thereby accelerating the synthesis and secretion of type III collagen (Col III) at the early stage. Finally, the promoted rapid transformation of Col III to Col I at late stage benefits the bone regeneration. Hence, this study can provide a theoretical basis for the local application of MY-1 in bone regeneration.
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Affiliation(s)
- Zhang Yanli
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Mo Jiayao
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Zheng Chunqing
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Zeng Yuting
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Zhou Zhiyan
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Zhang Yulin
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Li Minghan
- Department of Orthopedics - Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Shao Longquan
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Yang Dehong
- Department of Orthopedics - Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Yan Wenjuan
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
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Li G, Shen W, Chu M, Mo G, Yao L, Xu W. Effect of inoculation density of bone marrow mesenchymal stem cells cultured on calcium phosphate cement scaffold on osteogenic differentiation. Biomed Mater Eng 2023; 34:111-121. [PMID: 35871314 DOI: 10.3233/bme-221394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Calcium phosphate cements (CPCs) are biocompatible materials that have been evaluated as scaffolds in bone tissue engineering. At present, the stem cell density of inoculation on CPC scaffold varies. OBJECTIVE The aim of this study is to analyze the effect of seeding densities on cell growth and osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) on a calcium phosphate cements (CPCs) scaffold. METHODS BMMSCs derived from minipigs were seeded onto a CPC scaffold at three densities [1 million/mL (1M), 5 million/mL (5M) and 25 million/mL 25M)], and cultured for osteogenic induction for 1, 4 and 8 days. RESULTS Well adhered and extended BMMSCs on the CPC scaffold showed significantly different proliferation rates within each seeding density group at different time points (P < 0.05). The number of live cells per unit area in 1M, 5M and 25M increased by 3.5, 3.9 and 2.5 folds respectively. The expression of ALP peaked at 4 days post inoculation with the fold-change being 2.6 and 2.8 times higher in 5M and 25M respectively as compared to 1M. The expression levels of OC, Coll-1 and Runx-2 peaked at 8 days post inoculation. CONCLUSIONS An optimal seeding density may be more conducive for cell proliferation, differentiation, and extracellular matrix synthesis on scaffolds. We suggest the optimal seeding density should be 5 million/mL.
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Affiliation(s)
- Guangjun Li
- Department of Orthopedics, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Wen Shen
- Department of Radiology, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Minghui Chu
- Department of Orthopedics, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Guowei Mo
- Department of Orthopedics, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Liqin Yao
- Department of Orthopedics, Deqing People's Hospital, Deqing, Zhejiang, China
| | - Weidong Xu
- Department of Orthopedics, Deqing People's Hospital, Deqing, Zhejiang, China
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Gao P, Liu S, Wang X, Ikeya M. Dental applications of induced pluripotent stem cells and their derivatives. JAPANESE DENTAL SCIENCE REVIEW 2022; 58:162-171. [PMID: 35516907 PMCID: PMC9065891 DOI: 10.1016/j.jdsr.2022.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 02/24/2022] [Accepted: 03/17/2022] [Indexed: 11/26/2022] Open
Abstract
Periodontal tissue regeneration is the ideal tactic for treating periodontitis. Tooth regeneration is the potential strategy to restore the lost teeth. With infinite self-renewal, broad differentiation potential, and less ethical issues than embryonic stem cells, induced pluripotent stem cells (iPSCs) are promising cell resource for periodontal and tooth regeneration. This review summarized the optimized technologies of generating iPSC lines and application of iPSC derivatives, which reduce the risk of tumorigenicity. Given that iPSCs may have epigenetic memory from the donor tissue and tend to differentiate into lineages along with the donor cells, iPSCs derived from dental tissues may benefit for personalized dental application. Neural crest cells (NCCs) and mesenchymal stem or stomal cells (MSCs) are lineage-specific progenitor cells derived from iPSCs and can differentiate into multilineage cell types. This review introduced the updated technologies of inducing iPSC-derived NCCs and iPSC-derived MSCs and their application in periodontal and tooth regeneration. Given the complexity of periodontal tissues and teeth, it is crucial to elucidate the integrated mechanisms of all constitutive cells and the spatio-temporal interactions among them to generate structural periodontal tissues and functional teeth. Thus, more sophisticated studies in vitro and in vivo and even preclinical investigations need to be conducted.
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Affiliation(s)
- Pan Gao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of General and Emergency Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shan Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Division of Oral Ecology and Biochemistry, Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Xiaoyi Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Makoto Ikeya
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Wu YX, Mao QY, Kang YF, Xie S, Shan XF, Cai ZG. In Vivo Oral Sentinel Lymph Node Mapping by Near-Infrared Fluorescent Methylene Blue in Rats. Diagnostics (Basel) 2022; 12:diagnostics12112574. [PMID: 36359418 PMCID: PMC9689899 DOI: 10.3390/diagnostics12112574] [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: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022] Open
Abstract
This study aimed to demonstrate the feasibility of near-infrared (NIR) fluorescence imaging using methylene blue (MB) for detecting oral sentinel lymph nodes (SLNs) in rats and compared MB’s tracer effects with those of indocyanine green (ICG) in SLN mapping. Different concentrations of MB were injected into the rats’ left lingual submucosa to determine the optimal concentration by using a continuous (1 h) MI-1 fluorescence imaging system. To compare the tracer effects of the optimal MB concentration with ICG in oral SLN mapping, MI-1 imaging was continuously monitored for 12 h. The mean signal-to-background ratio (SBR) of the SLNs and SLN fluorescence area fraction were analyzed. SLNs and lymphatic vessels were clearly visible in all rats. The optimal injection dose of MB infected into lingual submucosa for NIR fluorescence imaging was 0.2 mL of 6.68 mM MB. During continuous monitoring for 12 h, the mean SBR of the SLNs was significantly higher in the ICG groups than in the MB groups (p < 0.001). However, the area fraction of SLN fluorescence in the ICG groups increased continuously, owing to strong fluorescent contamination. This study examined the feasibility of detection of draining lymph nodes in the oral cavity of rats using MB NIR fluorescence imaging. MB causes less fluorescent contamination than does ICG, which shows promise for clinical research and application.
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Affiliation(s)
- Yu-Xiao Wu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Qian-Ying Mao
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Yi-Fan Kang
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Shang Xie
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Xiao-Feng Shan
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Zhi-Gang Cai
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
- National Center of Stomatology, Beijing 100081, China
- National Clinical Research Center for Oral Diseases, Beijing 100081, China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
- Correspondence: ; Tel.: +86-13910733943; Fax: +86-10-62173402
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Hua Z, Li S, Liu Q, Yu M, Liao M, Zhang H, Xiang X, Wu Q. Low-Intensity Pulsed Ultrasound Promotes Osteogenic Potential of iPSC-Derived MSCs but Fails to Simplify the iPSC-EB-MSC Differentiation Process. Front Bioeng Biotechnol 2022; 10:841778. [PMID: 35656194 PMCID: PMC9152674 DOI: 10.3389/fbioe.2022.841778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/07/2022] [Indexed: 11/29/2022] Open
Abstract
Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) are a promising cell source for bone tissue engineering. However, iMSCs have less osteogenic potential than BMSCs, and the classical iPSC-EB-iMSC process to derive iMSCs from iPSCs is too laborious as it involves multiple in vitro steps. Low-intensity pulsed ultrasound (LIPUS) is a safe therapeutic modality used to promote osteogenic differentiation of stem cells. Whether LIPUS can facilitate osteogenic differentiation of iMSCs and simplify the iPSC-EB-iMSC process is unknown. We stimulated iMSCs with LIPUS at different output intensities (20, 40, and 60 mW/cm2) and duty cycles (20, 50, and 80%). Results of ALP activity assay, osteogenic gene expression, and mineralization quantification demonstrated that LIPUS was able to promote osteogenic differentiation of iMSCs, and it worked best at the intensity of 40 mW/cm2 and the duty cycle of 50% (LIPUS40/50). The Wnt/β-catenin signaling pathway was involved in LIPUS40/50-mediated osteogenesis. When cranial bone defects were implanted with iMSCs, LIPUS40/50 stimulation resulted in a significant higher new bone filling rate (72.63 ± 17.04)% than the non-stimulated ones (34.85 ± 4.53)%. Daily exposure to LIPUS40/50 may accelerate embryoid body (EB)-MSC transition, but it failed to drive iPSCs or EB cells to an osteogenic lineage directly. This study is the first to demonstrate the pro-osteogenic effect of LIPUS on iMSCs. Although LIPUS40/50 failed to simplify the classical iPSC-EB-MSC differentiation process, our preliminary results suggest that LIPUS with a more suitable parameter set may achieve the goal. LIPUS is a promising method to establish an efficient model for iPSC application.
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Affiliation(s)
| | | | | | | | | | | | | | - Qingqing Wu
- *Correspondence: Qingqing Wu, ; Xuerong Xiang,
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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8
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Liu TM. Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine. World J Stem Cells 2021; 13:1826-1844. [PMID: 35069985 PMCID: PMC8727229 DOI: 10.4252/wjsc.v13.i12.1826] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/29/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) represent the most clinically used stem cells in regenerative medicine. However, due to the disadvantages with primary MSCs, such as limited cell proliferative capacity and rarity in the tissues leading to limited MSCs, gradual loss of differentiation during in vitro expansion reducing the efficacy of MSC application, and variation among donors increasing the uncertainty of MSC efficacy, the clinical application of MSCs has been greatly hampered. MSCs derived from human pluripotent stem cells (hPSC-MSCs) can circumvent these problems associated with primary MSCs. Due to the infinite self-renewal of hPSCs and their differentiation potential towards MSCs, hPSC-MSCs are emerging as an attractive alternative for regenerative medicine. This review summarizes the progress on derivation of MSCs from human pluripotent stem cells, disease modelling and drug screening using hPSC-MSCs, and various applications of hPSC-MSCs in regenerative medicine. In the end, the challenges and concerns with hPSC-MSC applications are also discussed.
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Affiliation(s)
- Tong-Ming Liu
- Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Singapore 138648, Singapore.
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Pluripotent-derived Mesenchymal Stem/stromal Cells: an Overview of the Derivation Protocol Efficacies and the Differences Among the Derived Cells. Stem Cell Rev Rep 2021; 18:94-125. [PMID: 34545529 DOI: 10.1007/s12015-021-10258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are remarkable tools for regenerative medicine. Therapeutic approaches using these cells can promote increased activity and viability in several cell types through diverse mechanisms such as paracrine and immunomodulatory activities, contributing substantially to tissue regeneration and functional recovery. However, biological samples of human MSCs, usually obtained from adult tissues, often exhibit variable behavior during in vitro culture, especially with respect to cell population heterogeneity, replicative senescence, and consequent loss of functionality. Accordingly, it is necessary to establish standard protocols to generate high-quality, stable cell cultures, for example, by using pluripotent stem cells (PSCs) in derivation protocols of MSC-like cells since PSCs maintain their characteristics consistently during culture. However, the available protocols seem to generate distinct populations of PSC-derivedMSCs (PSC-MSCs) with peculiar attributes, which do not always resemble bona fide primary MSCs. The present review addresses the developmental basis behind some of these derivation protocols, exposing the differences among them and discussing the functional properties of PSC-MSCs, shedding light on elements that may help determine standard characterizations and criteria to evaluate and define these cells.
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10
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Li C, Mills Z, Zheng Z. Novel cell sources for bone regeneration. MedComm (Beijing) 2021; 2:145-174. [PMID: 34766140 PMCID: PMC8491221 DOI: 10.1002/mco2.51] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/03/2020] [Accepted: 12/09/2020] [Indexed: 01/09/2023] Open
Abstract
A plethora of both acute and chronic conditions, including traumatic, degenerative, malignant, or congenital disorders, commonly induce bone disorders often associated with severe persisting pain and limited mobility. Over 1 million surgical procedures involving bone excision, bone grafting, and fracture repair are performed each year in the U.S. alone, resulting in immense levels of public health challenges and corresponding financial burdens. Unfortunately, the innate self-healing capacity of bone is often inadequate for larger defects over a critical size. Moreover, as direct transplantation of committed osteoblasts is hindered by deficient cell availability, limited cell spreading, and poor survivability, an urgent need for novel cell sources for bone regeneration is concurrent. Thanks to the development in stem cell biology and cell reprogramming technology, many multipotent and pluripotent cells that manifest promising osteogenic potential are considered the regenerative remedy for bone defects. Considering these cells' investigation is still in its relative infancy, each of them offers their own particular challenges that must be conquered before the large-scale clinical application.
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Affiliation(s)
- Chenshuang Li
- Department of Orthodontics, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Zane Mills
- College of DentistryUniversity of OklahomaOklahoma CityOklahomaUSA
| | - Zhong Zheng
- Division of Growth and Development, School of DentistryUniversity of CaliforniaLos AngelesCaliforniaUSA
- Department of Surgery, David Geffen School of MedicineUniversity of CaliforniaLos AngelesCaliforniaUSA
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11
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Song B, Fu H, Liu J, Ren K, Weir MD, Schneider A, Wang P, Song Y, Zhao L, Xu H. Bioactive small molecules in calcium phosphate scaffold enhanced osteogenic differentiation of human induced pluripotent stem cells. Dent Mater J 2021; 40:615-624. [PMID: 33814531 DOI: 10.4012/dmj.2019-263] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Human induced pluripotent stem cells (hiPSCs) are exciting for regenerative medicine due to their multi-potent differentiation. SB431542 bioactive molecule can activate bone morphogenetic protein-signalling in osteoblasts. The objectives were to: (1) develop a novel injectable calcium phosphate cement (CPC)-SB431542 scaffold for dental/craniofacial bone engineering; and (2) investigate cell proliferation and osteo-differentiation of hiPSC-derived mesenchymal stem cells (hiPSC-MSCs) on CPC-SB431542 scaffold. Three groups were tested: CPC control; CPC with SB431542 inside CPC (CPCSM); CPC with SB431542 in osteogenic medium (CPC+SMM). SB431542 in CPC promoted stem cell proliferation and viability. hiPSC-MSCs differentiated into osteogenic lineage and synthesized bone minerals. CPC with SB431542 showed much greater osteo-expressions and more bone minerals than those without SB431542. In conclusion, hiPSC-MSCs on CPC scaffold containing SB431542 showed excellent osteo-differentiation and bone mineral synthesis for the first time. CPC was a suitable scaffold for delivering stem cells and SB431542 to promote bone regeneration in dental/craniofacial applications.
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Affiliation(s)
- Bing Song
- Department of Orthopedic Surgery, Shunde Hospital of Southern Medical University.,Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry
| | - Haijun Fu
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology
| | - Jianwei Liu
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology
| | - Ke Ren
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry
| | - Michael D Weir
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry
| | - Abraham Schneider
- Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry
| | - Ping Wang
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry
| | - Yang Song
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry.,Department of Prosthodontics, Guanghua School of Stomatology, Sun Yat-sen University
| | - Liang Zhao
- Department of Orthopedic Surgery, Shunde Hospital of Southern Medical University.,Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry
| | - Huakun Xu
- Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry.,Center for Stem Cell Biology and Regenerative Medicine, University of Maryland School of Medicine.,University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine
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12
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Li J, Lin Q, Lin Y, Lai R, Zhang W. Effects of DLX3 on the osteogenic differentiation of induced pluripotent stem cell‑derived mesenchymal stem cells. Mol Med Rep 2021; 23:232. [PMID: 33655330 PMCID: PMC7893805 DOI: 10.3892/mmr.2021.11871] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 12/02/2020] [Indexed: 12/31/2022] Open
Abstract
Osteoporosis is a disease characterized by the degeneration of bone structure and decreased bone mass. Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) have multiple advantages that make them ideal seed cells for bone regeneration, including high-level proliferation, multi-differentiation potential and favorable immune compatibility. Distal-less homeobox (DLX)3, an important member of the DLX family, serves a crucial role in osteogenic differentiation and bone formation. The present study aimed to evaluate the effects of DLX3 on the proliferation and osteogenic differentiation of human iPSC-MSCs. iPSC-MSCs were induced from iPSCs, and identified via flow cytometry. Alkaline phosphatase (ALP), Von Kossa, Oil Red O and Alcian blue staining methods were used to evaluate the osteogenic, adipogenic and chondrogenic differentiation of iPSC-MSCs. DLX3 overexpression plasmids were constructed and transfected into iPSC-MSCs to generate iPSC-MSC-DLX3. iPSC-MSC-GFP was used as the control. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to measure the expression of DLX3 2 days after transfection. Subsequently, cell proliferation was assessed using a Cell Counting Kit-8 assay on days 1, 3, 5 and 7. RT-qPCR and western blotting were used to analyze osteogenic-related gene and protein expression levels on day 7. ALP activity and mineralized nodules were assessed via ALP staining on day 14. Statistical analysis was performed using an unpaired Student's t-test. Flow cytometry results demonstrated that iPSC-MSCs were positive for CD73, CD90 and CD105, but negative for CD34 and CD45. iPSC-MSC-DLX3 had significantly lower proliferation compared with iPSC-MSC-GFP on days 5 and 7 (P<0.05). mRNA expression levels of osteogenic markers, such as ALP, osteopenia (OPN), osteocalcin (OCN) and Collagen Type I (COL-1), were significantly increased in iPSC-MSC-DLX3 compared with iPSC-MSC-GFP on day 7 (P<0.05). Similarly, the protein expression levels of ALP, OCN, OPN and COL-1 were significantly increased in iPSC-MSC-DLX3 compared with iPSC-MSC-GFP on day 7 (P<0.05). The number of mineralized nodules in iPSC-MSC-DLX3 was increased compared with that in iPSC-MSC-GFP on day 14 (P<0.05). Thus, the present study demonstrated that DLX3 serves a negative role in proliferation, but a positive role in the osteogenic differentiation of iPSC-MSCs. This may provide novel insight for treating osteoporosis.
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Affiliation(s)
- Junyuan Li
- The Medical Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Qiang Lin
- The Medical Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Yixin Lin
- The Medical Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Renfa Lai
- The Medical Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Wen Zhang
- Department of Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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13
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Jamal M, Bashir A, Al-Sayegh M, Huang GTJ. Oral tissues as sources for induced pluripotent stem cell derivation and their applications for neural, craniofacial, and dental tissue regeneration. CELL SOURCES FOR IPSCS 2021:71-106. [DOI: 10.1016/b978-0-12-822135-8.00007-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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14
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Induced Pluripotent Stem Cells in Dental and Nondental Tissue Regeneration: A Review of an Unexploited Potential. Stem Cells Int 2020; 2020:1941629. [PMID: 32300365 PMCID: PMC7146092 DOI: 10.1155/2020/1941629] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/06/2020] [Indexed: 12/16/2022] Open
Abstract
Cell-based therapies currently represent the state of art for tissue regenerative treatment approaches for various diseases and disorders. Induced pluripotent stem cells (iPSCs), reprogrammed from adult somatic cells, using vectors carrying definite transcription factors, have manifested a breakthrough in regenerative medicine, relying on their pluripotent nature and ease of generation in large amounts from various dental and nondental tissues. In addition to their potential applications in regenerative medicine and dentistry, iPSCs can also be used in disease modeling and drug testing for personalized medicine. The current review discusses various techniques for the production of iPSC-derived osteogenic and odontogenic progenitors, the therapeutic applications of iPSCs, and their regenerative potential in vivo and in vitro. Through the present review, we aim to explore the potential applications of iPSCs in dental and nondental tissue regeneration and to highlight different protocols used for the generation of different tissues and cell lines from iPSCs.
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15
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Raju R, Oshima M, Inoue M, Morita T, Huijiao Y, Waskitho A, Baba O, Inoue M, Matsuka Y. Three-dimensional periodontal tissue regeneration using a bone-ligament complex cell sheet. Sci Rep 2020; 10:1656. [PMID: 32015383 PMCID: PMC6997427 DOI: 10.1038/s41598-020-58222-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023] Open
Abstract
Periodontal tissue is a distinctive tissue structure composed three-dimensionally of cementum, periodontal ligament (PDL) and alveolar bone. Severe periodontal diseases cause fundamental problems for oral function and general health, and conventional dental treatments are insufficient for healing to healthy periodontal tissue. Cell sheet technology has been used in many tissue regenerations, including periodontal tissue, to transplant appropriate stem/progenitor cells for tissue regeneration of a target site as a uniform tissue. However, it is still difficult to construct a three-dimensional structure of complex tissue composed of multiple types of cells, and the transplantation of a single cell sheet cannot sufficiently regenerate a large-scale tissue injury. Here, we fabricated a three-dimensional complex cell sheet composed of a bone-ligament structure by layering PDL cells and osteoblast-like cells on a temperature responsive culture dish. Following ectopic and orthotopic transplantation, only the complex cell sheet group was demonstrated to anatomically regenerate the bone-ligament structure along with the functional connection of PDL-like fibers to the tooth root and alveolar bone. This study represents successful three-dimensional tissue regeneration of a large-scale tissue injury using a bioengineered tissue designed to simulate the anatomical structure.
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Affiliation(s)
- Resmi Raju
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Masamitsu Oshima
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Miho Inoue
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Tsuyoshi Morita
- Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Yan Huijiao
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Arief Waskitho
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Otto Baba
- Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Masahisa Inoue
- Laboratories for Structure and Function Research, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8055, Japan
| | - Yoshizo Matsuka
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan.
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16
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Wang AYL, Loh CYY. Episomal Induced Pluripotent Stem Cells: Functional and Potential Therapeutic Applications. Cell Transplant 2019; 28:112S-131S. [PMID: 31722555 PMCID: PMC7016470 DOI: 10.1177/0963689719886534] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 06/11/2019] [Accepted: 10/07/2019] [Indexed: 12/19/2022] Open
Abstract
The term episomal induced pluripotent stem cells (EiPSCs) refers to somatic cells that are reprogrammed into induced pluripotent stem cells (iPSCs) using non-integrative episomal vector methods. This reprogramming process has a better safety profile compared with integrative methods using viruses. There is a current trend toward using episomal plasmid reprogramming to generate iPSCs because of the improved safety profile. Clinical reports of potential human cell sources that have been successfully reprogrammed into EiPSCs are increasing, but no review or summary has been published. The functional applications of EiPSCs and their potential uses in various conditions have been described, and these may be applicable to clinical scenarios. This review summarizes the current direction of EiPSC research and the properties of these cells with the aim of explaining their potential role in clinical applications and functional restoration.
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Affiliation(s)
- Aline Yen Ling Wang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- *Both the authors contributed equally to this article
| | - Charles Yuen Yung Loh
- St Andrew’s Center for Burns and Plastic Surgery, Chelmsford, United Kingdom
- *Both the authors contributed equally to this article
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17
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Fliefel R, Ehrenfeld M, Otto S. Induced pluripotent stem cells (iPSCs) as a new source of bone in reconstructive surgery: A systematic review and meta-analysis of preclinical studies. J Tissue Eng Regen Med 2018; 12:1780-1797. [DOI: 10.1002/term.2697] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 04/16/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Riham Fliefel
- Experimental Surgery and Regenerative Medicine (ExperiMed), Faculty of Medicine; Ludwig Maximilian University of Munich; Munich Germany
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine; Ludwig Maximilian University of Munich; Munich Germany
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry; Alexandria University; Alexandria Egypt
| | - Michael Ehrenfeld
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine; Ludwig Maximilian University of Munich; Munich Germany
| | - Sven Otto
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine; Ludwig Maximilian University of Munich; Munich Germany
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18
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Hasan A, Byambaa B, Morshed M, Cheikh MI, Shakoor RA, Mustafy T, Marei HE. Advances in osteobiologic materials for bone substitutes. J Tissue Eng Regen Med 2018; 12:1448-1468. [DOI: 10.1002/term.2677] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 02/04/2018] [Accepted: 04/12/2018] [Indexed: 01/03/2023]
Affiliation(s)
- Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering; Qatar University; Doha Qatar
| | - Batzaya Byambaa
- Center for Biomedical Engineering, Department of Medicine; Brigham and Women's Hospital, Harvard Medical School; Cambridge MA USA
- Harvard-MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology; Cambridge MA USA
| | - Mahboob Morshed
- School of Life Sciences; Independent University, Bangladesh (IUB); Dhaka Bangladesh
| | - Mohammad Ibrahim Cheikh
- Department of Mechanical Engineering, Faculty of Engineering and Architecture; American University of Beirut; Beirut Lebanon
| | | | - Tanvir Mustafy
- Department of Mechanical Engineering; Ecole Polytechnique de Montreal; Quebec Canada
| | - Hany E. Marei
- Biomedical Research Center; Qatar University; Doha Qatar
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19
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Stem Cells for Osteochondral Regeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1059:219-240. [DOI: 10.1007/978-3-319-76735-2_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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20
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Qiu J, Zhang HY, Liu L, Tan YH. [Effect of bone morphogenetic protein-4 overexpression on the biological activity of mouse induced pluripotent stem cells]. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2018; 36:190-193. [PMID: 29779282 PMCID: PMC7030344 DOI: 10.7518/hxkq.2018.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/09/2017] [Indexed: 11/21/2022]
Abstract
OBJECTIVE This study aimed to construct the expression of bone morphogenetic protein-4 (BMP4) lentiviral vector gene and explore its influence on the biological activity of mouse induced pluripotent stem (iPS) cells. METHODS iPS cell lines stably overexpressing BMP4 were constructed by lentivirus transfection (BMP4-overexpressing group). Cells without transfection served as the blank group, and cells with only vector transfection served as the empty-vector group. Cell proliferation was detected by CCK8, and the expression levels of ameloblastin (AMBN), cytokeratin (CK) 14, dentin sialophospho-protein (DSPP), bone sialoprotein (BSP), and Runx2 mRNA were detected by quantitative polymerase chain reaction. Alkaline phosphatase (ALP) activity was used to detect the degree of cell differentiation. RESULTS Compared with blank and empty-vector groups, proliferation activity and ALP activity of BMP4-overexpressing group obvious increased (P<0.05), BMP4, AMBN, CK14, DSPP, BSP, Runx2 mRNA expression also increased (P<0.05). CONCLUSIONS BMP4 can significantly promote the odontogenic differentiation of iPS.
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Affiliation(s)
- Jin Qiu
- Dept. of Stomatology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China
| | - Hui-Yu Zhang
- Dept. of Stomatology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China
| | - Li Liu
- Dept. of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Ying-Hui Tan
- Dept. of Stomatology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China
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21
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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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22
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CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation. Oncotarget 2018; 7:29051-62. [PMID: 27074560 PMCID: PMC5045377 DOI: 10.18632/oncotarget.8665] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/28/2016] [Indexed: 02/05/2023] Open
Abstract
Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133− ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133− cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation.
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23
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Xu HHK, Wang P, Wang L, Bao C, Chen Q, Weir MD, Chow LC, Zhao L, Zhou X, Reynolds MA. Calcium phosphate cements for bone engineering and their biological properties. Bone Res 2017; 5:17056. [PMID: 29354304 PMCID: PMC5764120 DOI: 10.1038/boneres.2017.56] [Citation(s) in RCA: 217] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/13/2017] [Accepted: 08/09/2017] [Indexed: 02/08/2023] Open
Abstract
Calcium phosphate cements (CPCs) are frequently used to repair bone defects. Since their discovery in the 1980s, extensive research has been conducted to improve their properties, and emerging evidence supports their increased application in bone tissue engineering. Much effort has been made to enhance the biological performance of CPCs, including their biocompatibility, osteoconductivity, osteoinductivity, biodegradability, bioactivity, and interactions with cells. This review article focuses on the major recent developments in CPCs, including 3D printing, injectability, stem cell delivery, growth factor and drug delivery, and pre-vascularization of CPC scaffolds via co-culture and tri-culture techniques to enhance angiogenesis and osteogenesis.
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Affiliation(s)
- Hockin HK Xu
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
- Center for Stem Cell Biology and Regenerative
Medicine, University of Maryland School of Medicine, Baltimore,
MD
21201, USA
- University of Maryland Marlene and Stewart
Greenebaum Cancer Center, University of Maryland School of Medicine,
Baltimore, MD
21201, USA
- Mechanical Engineering Department, University
of Maryland Baltimore County, Baltimore, MD
21250, USA
| | - Ping Wang
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
- State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
Sichuan
610041, China
| | - Lin Wang
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
- VIP Integrated Department, Stomatological
Hospital of Jilin University, Changchun, Jilin
130011, China
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
Sichuan
610041, China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
Sichuan
610041, China
| | - Michael D Weir
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
| | - Laurence C Chow
- Volpe Research Center, American Dental
Association Foundation, National Institute of Standards & Technology,
Gaithersburg, MD
20899, USA
| | - Liang Zhao
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
- Department of Orthopaedic Surgery, Nanfang
Hospital, Southern Medical University, Guangzhou,
Guangdong
510515, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu,
Sichuan
610041, China
| | - Mark A Reynolds
- Department of Endodontics, Periodontics and
Prosthodontics, University of Maryland School of Dentistry,
Baltimore, MD
21201, USA
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Caddeo S, Boffito M, Sartori S. Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models. Front Bioeng Biotechnol 2017; 5:40. [PMID: 28798911 PMCID: PMC5526851 DOI: 10.3389/fbioe.2017.00040] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 06/26/2017] [Indexed: 12/16/2022] Open
Abstract
In the tissue engineering (TE) paradigm, engineering and life sciences tools are combined to develop bioartificial substitutes for organs and tissues, which can in turn be applied in regenerative medicine, pharmaceutical, diagnostic, and basic research to elucidate fundamental aspects of cell functions in vivo or to identify mechanisms involved in aging processes and disease onset and progression. The complex three-dimensional (3D) microenvironment in which cells are organized in vivo allows the interaction between different cell types and between cells and the extracellular matrix, the composition of which varies as a function of the tissue, the degree of maturation, and health conditions. In this context, 3D in vitro models can more realistically reproduce a tissue or organ than two-dimensional (2D) models. Moreover, they can overcome the limitations of animal models and reduce the need for in vivo tests, according to the "3Rs" guiding principles for a more ethical research. The design of 3D engineered tissue models is currently in its development stage, showing high potential in overcoming the limitations of already available models. However, many issues are still opened, concerning the identification of the optimal scaffold-forming materials, cell source and biofabrication technology, and the best cell culture conditions (biochemical and physical cues) to finely replicate the native tissue and the surrounding environment. In the near future, 3D tissue-engineered models are expected to become useful tools in the preliminary testing and screening of drugs and therapies and in the investigation of the molecular mechanisms underpinning disease onset and progression. In this review, the application of TE principles to the design of in vitro 3D models will be surveyed, with a focus on the strengths and weaknesses of this emerging approach. In addition, a brief overview on the development of in vitro models of healthy and pathological bone, heart, pancreas, and liver will be presented.
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Affiliation(s)
- Silvia Caddeo
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, Amsterdam, Netherlands
| | - Monica Boffito
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Susanna Sartori
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
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25
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Ardeshirylajimi A. Applied Induced Pluripotent Stem Cells in Combination With Biomaterials in Bone Tissue Engineering. J Cell Biochem 2017; 118:3034-3042. [DOI: 10.1002/jcb.25996] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 03/16/2017] [Indexed: 01/01/2023]
Affiliation(s)
- Abdolreza Ardeshirylajimi
- Department of Tissue Engineering and Applied Cell SciencesSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
- Edward A. Doisy Department of Biochemistry and Molecular BiologySaint Louis University School of MedicineSaint LouisMissouri
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26
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Bastami F, Nazeman P, Moslemi H, Rezai Rad M, Sharifi K, Khojasteh A. Induced pluripotent stem cells as a new getaway for bone tissue engineering: A systematic review. Cell Prolif 2017; 50:e12321. [PMID: 27905670 PMCID: PMC6529104 DOI: 10.1111/cpr.12321] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 10/31/2016] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) are frequently used for bone regeneration, however, they are limited in quantity. Moreover, their proliferation and differentiation capabilities reduce during cell culture expansion. Potential application of induced pluripotent stem cells (iPSCs) has been reported as a promising alternative source for bone regeneration. This study aimed to systematically review the available literature on osteogenic potential of iPSCs and to discuss methods applied to enhance their osteogenic potential. METHODS AND MATERIALS A thorough search of MEDLINE database was performed from January 2006 to September 2016, limited to English-language articles. All in vitro and in vivo studies on application of iPSCs in bone regeneration were included. RESULTS The current review is organized according to the PRISMA statement. Studies were categorized according to three different approaches used for osteo-induction of iPSCs. Data are summarized and reported according to the following variables: types of study, cell sources used for iPSC generation, applied reprogramming methods, applied osteo-induction methods and treatment groups. CONCLUSION According to the articles reviewed, osteo-induced iPSCs revealed osteogenic capability equal to or superior than MSCs; cell sources do not significantly affect osteogenic potential of iPSCs; addition of resveratrol to the osteogenic medium (OM) and irradiatiation after osteogenic induction reduce teratoma formation in animal models; transfection with lentiviral bone morphogenetic protein 2 results in higher mineralization compared to osteo-induction in OM; addition of TGF-β, IGF-1 and FGF-β to OM increases osteogenic capability of iPSCs.
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Affiliation(s)
- Farshid Bastami
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Pantea Nazeman
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Hamidreza Moslemi
- School of DentistryShahid Beheshti University of Medical SciencesTehranIran
| | - Maryam Rezai Rad
- Medical Nano‐Technology & Tissue Engineering Research CenterSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Kazem Sharifi
- Department of BiotechnologySchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Arash Khojasteh
- Department of Tissue EngineeringSchool of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
- Faculty of MedicineUniversity of AntwerpAntwerpBelgium
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Mesenchymal Stem and Progenitor Cells in Regeneration: Tissue Specificity and Regenerative Potential. Stem Cells Int 2017; 2017:5173732. [PMID: 28286525 PMCID: PMC5327785 DOI: 10.1155/2017/5173732] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 12/07/2016] [Indexed: 12/15/2022] Open
Abstract
It has always been an ambitious goal in medicine to repair or replace morbid tissues for regaining the organ functionality. This challenge has recently gained momentum through considerable progress in understanding the biological concept of the regenerative potential of stem cells. Routine therapeutic procedures are about to shift towards the use of biological and molecular armamentarium. The potential use of embryonic stem cells and invention of induced pluripotent stem cells raised hope for clinical regenerative purposes; however, the use of these interventions for regenerative therapy showed its dark side, as many health concerns and ethical issues arose in terms of using these cells in clinical applications. In this regard, adult stem cells climbed up to the top list of regenerative tools and mesenchymal stem cells (MSC) showed promise for regenerative cell therapy with a rather limited level of risk. MSC have been successfully isolated from various human tissues and they have been shown to offer the possibility to establish novel therapeutic interventions for a variety of hard-to-noncurable diseases. There have been many elegant studies investigating the impact of MSC in regenerative medicine. This review provides compact information on the role of stem cells, in particular, MSC in regeneration.
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Jahan K, Tabrizian M. Composite biopolymers for bone regeneration enhancement in bony defects. Biomater Sci 2017; 4:25-39. [PMID: 26317131 DOI: 10.1039/c5bm00163c] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
For the past century, various biomaterials have been used in the treatment of bone defects and fractures. Their role as potential substitutes for human bone grafts increases as donors become scarce. Metals, ceramics and polymers are all materials that confer different advantages to bone scaffold development. For instance, biocompatibility is a highly desirable property for which naturally-derived polymers are renowned. While generally applied separately, the use of biomaterials, in particular natural polymers, is likely to change, as biomaterial research moves towards mixing different types of materials in order to maximize their individual strengths. This review focuses on osteoconductive biocomposite scaffolds which are constructed around natural polymers and their performance at the in vitro/in vivo stages and in clinical trials.
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Affiliation(s)
- K Jahan
- Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC H3A 2B2, Canada.
| | - M Tabrizian
- Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC H3A 2B2, Canada. and Biomedical Engineering, Duff Medical Building, Room 313, McGill, Montreal, H3A 2B4, Canada
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29
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Jeon OH, Elisseeff J. Orthopedic tissue regeneration: cells, scaffolds, and small molecules. Drug Deliv Transl Res 2016; 6:105-20. [PMID: 26625850 DOI: 10.1007/s13346-015-0266-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Orthopedic tissue regeneration would benefit the aging population or patients with degenerative bone and cartilage diseases, especially osteoporosis and osteoarthritis. Despite progress in surgical and pharmacological interventions, new regenerative approaches are needed to meet the challenge of creating bone and articular cartilage tissues that are not only structurally sound but also functional, primarily to maintain mechanical integrity in their high load-bearing environments. In this review, we discuss new advances made in exploiting the three classes of materials in bone and cartilage regenerative medicine--cells, biomaterial-based scaffolds, and small molecules--and their successes and challenges reported in the clinic. In particular, the focus will be on the development of tissue-engineered bone and cartilage ex vivo by combining stem cells with biomaterials, providing appropriate structural, compositional, and mechanical cues to restore damaged tissue function. In addition, using small molecules to locally promote regeneration will be discussed, with potential approaches that combine bone and cartilage targeted therapeutics for the orthopedic-related disease, especially osteoporosis and osteoarthritis.
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Affiliation(s)
- Ok Hee Jeon
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, 5031 Smith Building, 400N. Broadway, Baltimore, MD, 21231, USA
| | - Jennifer Elisseeff
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, 5031 Smith Building, 400N. Broadway, Baltimore, MD, 21231, USA.
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30
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Sladkova M, Palmer M, Öhman C, Alhaddad RJ, Esmael A, Engqvist H, de Peppo GM. Fabrication of macroporous cement scaffolds using PEG particles: In vitro evaluation with induced pluripotent stem cell-derived mesenchymal progenitors. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 69:640-52. [DOI: 10.1016/j.msec.2016.06.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/07/2016] [Accepted: 06/23/2016] [Indexed: 02/02/2023]
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Malhotra N. Induced Pluripotent Stem (iPS) Cells in Dentistry: A Review. Int J Stem Cells 2016; 9:176-185. [PMID: 27572712 PMCID: PMC5155713 DOI: 10.15283/ijsc16029] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2016] [Indexed: 12/15/2022] Open
Abstract
iPS cells are derived from somatic cells via transduction and expression of selective transcription factors. Both viral-integrating (like retroviral) and non-integrating (like, mRNA or protein-based) techniques are available for the production of iPS cells. In the field of dentistry, iPS cells have been derived from stem cells of apical papilla, dental pulp stem cells, and stem cells from exfoliated deciduous teeth, gingival and periodontal ligament fibroblasts, and buccal mucosa fibroblasts. iPS cells have the potential to differentiate into all derivatives of the 3 primary germ layers i.e. ectoderm, endoderm, and mesoderm. They are autogeneically accessible, and can produce patient-specific or disease-specific cell lines without the issue of ethical controversy. They have been successfully tested to produce mesenchymal stem cells-like cells, neural crest-like cells, ameloblasts-like cells, odontoblasts-like cells, and osteoprogenitor cells. These cells can aid in regeneration of periodontal ligament, alveolar bone, cementum, dentin-pulp complex, as well as possible Biotooth formation. However certain key issues like, epigenetic memory of iPS cells, viral-transduction, tumorgenesis and teratoma formation need to be overcome, before they can be successfully used in clinical practice. The article discusses the sources, pros and cons, and current applications of iPS cells in dentistry with an emphasis on encountered challenges and their solutions.
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Affiliation(s)
- Neeraj Malhotra
- Department of Conservative Dentistry and Endodontics, Faculty of Dentistry, SEGi University, Kota Damansara, Selangor, Malaysia
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32
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Wu Q, Yang B, Hu K, Cao C, Man Y, Wang P. Deriving Osteogenic Cells from Induced Pluripotent Stem Cells for Bone Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2016; 23:1-8. [PMID: 27392674 DOI: 10.1089/ten.teb.2015.0559] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Induced pluripotent stem cells (iPSCs), reprogrammed from adult somatic cells using defined transcription factors, are regarded as a promising cell source for tissue engineering. For the purpose of bone tissue regeneration, efficient in vitro differentiation of iPSCs into downstream cells, such as mesenchymal stem cells (MSCs), osteoblasts, or osteocyte-like cells, before use is necessary to limit undesired tumorogenesis associated with the pluripotency of iPSCs. Until recently numerous techniques on the production of iPSC-derived osteogenic progenitors have been introduced. We reviewed these protocols and provided a perspective on the comparisons of osteogenic potentials of (1) iPSC-derived osteogenic cells produced by different protocols, (2) iPSCs from different somatic origins, and (3) iPSC-derived MSC-like cells and bone marrow stem cells. Finally, we discussed the potential application of the diseased iPSCs for systematic bone disorders.
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Affiliation(s)
- Qingqing Wu
- 1 State Key Laboratory of Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University , Chengdu, China
| | - Bo Yang
- 1 State Key Laboratory of Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University , Chengdu, China
| | - Kevin Hu
- 2 University of Maryland Dental School , Baltimore, Maryland
| | - Cong Cao
- 3 Department of Stomatology, China-Japan Friendship Hospital , Beijing, China
| | - Yi Man
- 1 State Key Laboratory of Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University , Chengdu, China
| | - Ping Wang
- 1 State Key Laboratory of Oral Diseases, Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University , Chengdu, China .,2 University of Maryland Dental School , Baltimore, Maryland
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33
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Jeon OH, Panicker LM, Lu Q, Chae JJ, Feldman RA, Elisseeff JH. Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. Sci Rep 2016; 6:26761. [PMID: 27225733 PMCID: PMC4881234 DOI: 10.1038/srep26761] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 05/03/2016] [Indexed: 12/17/2022] Open
Abstract
Bone substitutes can be designed to replicate physiological structure and function by creating a microenvironment that supports crosstalk between bone and immune cells found in the native tissue, specifically osteoblasts and osteoclasts. Human induced pluripotent stem cells (hiPSC) represent a powerful tool for bone regeneration because they are a source of patient-specific cells that can differentiate into all specialized cell types residing in bone. We show that osteoblasts and osteoclasts can be differentiated from hiPSC-mesenchymal stem cells and macrophages when co-cultured on hydroxyapatite-coated poly(lactic-co-glycolic acid)/poly(L-lactic acid) (HA–PLGA/PLLA) scaffolds. Both cell types seeded on the PLGA/PLLA especially with 5% w/v HA recapitulated the tissue remodeling process of human bone via coupling signals coordinating osteoblast and osteoclast activity and finely tuned expression of inflammatory molecules, resulting in accelerated in vitro bone formation. Following subcutaneous implantation in rodents, co-cultured hiPSC-MSC/-macrophage on such scaffolds showed mature bone-like tissue formation. These findings suggest the importance of coupling matrix remodeling through osteoblastic matrix deposition and osteoclastic tissue resorption and immunomodulation for tissue development.
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Affiliation(s)
- Ok Hee Jeon
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Leelamma M Panicker
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Qiaozhi Lu
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jeremy J Chae
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ricardo A Feldman
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jennifer H Elisseeff
- Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
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Sabapathy V, Kumar S. hiPSC-derived iMSCs: NextGen MSCs as an advanced therapeutically active cell resource for regenerative medicine. J Cell Mol Med 2016; 20:1571-88. [PMID: 27097531 PMCID: PMC4956943 DOI: 10.1111/jcmm.12839] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/14/2016] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are being assessed for ameliorating the severity of graft‐versus‐host disease, autoimmune conditions, musculoskeletal injuries and cardiovascular diseases. While most of these clinical therapeutic applications require substantial cell quantities, the number of MSCs that can be obtained initially from a single donor remains limited. The utility of MSCs derived from human‐induced pluripotent stem cells (hiPSCs) has been shown in recent pre‐clinical studies. Since adult MSCs have limited capability regarding proliferation, the quantum of bioactive factor secretion and immunomodulation ability may be constrained. Hence, the alternate source of MSCs is being considered to replace the commonly used adult tissue‐derived MSCs. The MSCs have been obtained from various adult and foetal tissues. The hiPSC‐derived MSCs (iMSCs) are transpiring as an attractive source of MSCs because during reprogramming process, cells undergo rejuvination, exhibiting better cellular vitality such as survival, proliferation and differentiations potentials. The autologous iMSCs could be considered as an inexhaustible source of MSCs that could be used to meet the unmet clinical needs. Human‐induced PSC‐derived MSCs are reported to be superior when compared to the adult MSCs regarding cell proliferation, immunomodulation, cytokines profiles, microenvironment modulating exosomes and bioactive paracrine factors secretion. Strategies such as derivation and propagation of iMSCs in chemically defined culture conditions and use of footprint‐free safer reprogramming strategies have contributed towards the development of clinically relevant cell types. In this review, the role of iPSC‐derived mesenchymal stromal cells (iMSCs) as an alternate source of therapeutically active MSCs has been described. Additionally, we also describe the role of iMSCs in regenerative medical applications, the necessary strategies, and the regulatory policies that have to be enforced to render iMSC's effectiveness in translational medicine.
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Affiliation(s)
- Vikram Sabapathy
- Center for Stem Cell Research, A Unit of inStem Bengaluru, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sanjay Kumar
- Center for Stem Cell Research, A Unit of inStem Bengaluru, Christian Medical College, Vellore, Tamil Nadu, India
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Ensuring the Quality of Stem Cell-Derived In Vitro Models for Toxicity Testing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 856:259-297. [DOI: 10.1007/978-3-319-33826-2_11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Luo X, Yang B, Sheng L, Chen J, Li H, Xie L, Chen G, Yu M, Guo W, Tian W. CAD based design sensitivity analysis and shape optimization of scaffolds for bio-root regeneration in swine. Biomaterials 2015; 57:59-72. [PMID: 25913251 DOI: 10.1016/j.biomaterials.2015.03.062] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 03/30/2015] [Accepted: 03/31/2015] [Indexed: 02/05/2023]
Abstract
Tooth root supports dental crown and bears occlusal force. While proper root shape and size render the force being evenly delivered and dispersed into jawbone. Yet it remains unclear what shape and size of a biological tooth root (bio-root), which is mostly determined by the scaffold geometric design, is suitable for stress distributing and mastication performing. Therefore, this study hypothesized scaffold fabricated in proper shape and size is better for regeneration of tooth root with approving biomechanical functional features. In this study, we optimized shape and size of scaffolds for bio-root regeneration using computer aided design (CAD) modeling and finite element analysis (FEA). Statical structural analysis showed the total deformation (TD) and equivalent von-mises stress (EQV) of the restored tooth model mainly concentrated on the scaffold and the post, in accordance with the condition in a natural post restored tooth. Design sensitivity analysis showed increasing the height and upper diameter of the scaffold can tremendously reduce the TD and EQV of the model, while increasing the bottom diameter of scaffold can, to some extent, reduce the EQV in post. However, increase on post height had little influence on the whole model, only slightly increased the native EQV stress in post. Through response surface based optimization, we successfully screened out the optimal shape of the scaffold used in tissue engineering of tooth root. The optimal scaffold adopted a slightly tapered shape with the upper diameter of 4.9 mm, bottom diameter of 3.4 mm; the length of the optimized scaffold shape was 9.4 mm. While the analysis also suggested a height of about 9 mm for a metal post with a diameter of 1.4 mm suitable for crown restoration in bio-root regeneration. In order to validate the physiological function of the shape optimized scaffold in vivo, we transplanted the shape optimized treated dentin matrix (TDM) scaffold, seeding with dental stem cells, into alveolar bone of swine and further installed porcelain crown. Results showed that tooth root has not only been successfully regenerated histologically but also performed masticatory function and maintained stable for three months after crown restoration. Our results suggested that TDM scaffold with 9.4 mm in length and 4.9 mm/3.4 mm in upper/bottom diameter is a suitable biological scaffold for tooth root regeneration. These results also provided a recommendable design protocol for fabricating other scaffolds in tooth root reconstruction.
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Affiliation(s)
- Xiangyou Luo
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Bo Yang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Lei Sheng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Jinlong Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Hui Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Li Xie
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Gang Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Mei Yu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Weihua Guo
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Pedodontics, West China College of Stomatology, Sichuan University, No.14, 3rd Section, Renmin South Road, Chengdu 610041, PR China.
| | - Weidong Tian
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
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Cheng PP, Liu XC, Ma PF, Gao C, Li JL, Lin YY, Shao W, Han S, Zhao B, Wang LM, Fu JZ, Meng LX, Li Q, Lian QZ, Xia JJ, Qi ZQ. iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation. Stem Cells Dev 2015; 24:1793-804. [PMID: 25867817 DOI: 10.1089/scd.2014.0488] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×10(6) iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (>100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4(+) and CD8(+) T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-β was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.
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Affiliation(s)
- Pan-Pan Cheng
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China .,2 Qingdao Municipal Centers for Disease Control and Prevention , Qingdao City, Shandong Province, People's Republic of China
| | - Xiao-Cun Liu
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Peng-Fei Ma
- 3 State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai City, People's Republic of China
| | - Chang Gao
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Jia-Li Li
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Ying-Ying Lin
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Wei Shao
- 4 The Affiliated Chenggong Hospital of Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Shuo Han
- 4 The Affiliated Chenggong Hospital of Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Bin Zhao
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Lu-Min Wang
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Jia-Zhao Fu
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Lu-Xi Meng
- 5 The First Affiliated Hospital of Xiamen University , Xiamen City, Fujian Province, People's of Republic of China
| | - Qing Li
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Qi-Zhou Lian
- 6 Departments of Ophthalmology and Medicine, University of Hong Kong , Pokfulam, Hong Kong, People's Republic of China
| | - Jun-Jie Xia
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
| | - Zhong-Quan Qi
- 1 Organ Transplantation Institute, Medical College, Xiamen University , Xiamen City, Fujian Province, People's Republic of China
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Beneficial effects of coculturing synovial derived mesenchymal stem cells with meniscus fibrochondrocytes are mediated by fibroblast growth factor 1: increased proliferation and collagen synthesis. Stem Cells Int 2015; 2015:926325. [PMID: 25852755 PMCID: PMC4379431 DOI: 10.1155/2015/926325] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 12/16/2014] [Accepted: 01/01/2015] [Indexed: 01/06/2023] Open
Abstract
Meniscus reconstruction is in great need for orthopedic surgeons. Meniscal fibrochondrocytes transplantation was proposed to regenerate functional meniscus, with limited donor supply. We hypothesized that coculture of synovial mesenchymal stem cells (SSC) with meniscal fibrochondrocytes (me-CH) can support matrix production of me-CH, thus reducing the number of me-CH needed for meniscus reconstruction. A pellet coculture system of human SSC and me-CH was used in this study. Enhanced glycosaminoglycans (GAG) in coculture pellets were demonstrated by Alcian blue staining and GAG quantification, when compared to monoculture. More collagen synthesis was shown in coculture pellets by hydroxyproline assay. Increased proliferation of me-CH was observed in coculture. Data from BrdU staining and ELISA demonstrated that conditioned medium of SSCs enhanced the proliferation and collagen synthesis of me-CH, and this effect was blocked by neutralizing antibody against fibroblast growth factor 1 (FGF1). Western blot showed that conditioned medium of SSCs can activate mitogen-activated protein kinase (MAPK) signaling pathways by increasing the phosphorylation of mitogen-activated regulated protein kinase 1/2 (MEK) and extracellular-signal-regulated kinases 1/2 (ERK). Overall, this study provided evidence that synovial MSCs can support proliferation and collagen synthesis of fibrochondrocytes, by secreting FGF1. Coimplantation of SSC and me-CH could be a useful strategy for reconstructing meniscus.
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Liu J, Chen W, Zhao Z, Xu HH. Effect of NELL1 gene overexpression in iPSC-MSCs seeded on calcium phosphate cement. Acta Biomater 2014; 10:5128-5138. [PMID: 25220281 DOI: 10.1016/j.actbio.2014.08.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 08/05/2014] [Accepted: 08/15/2014] [Indexed: 02/08/2023]
Abstract
Human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) are a promising source of patient-specific stem cells with great regenerative potential. There has been no report on NEL-like protein 1 (NELL1) gene modification of iPSC-MSCs. The objectives of this study were to genetically modify iPSC-MSCs with NELL1 overexpression for bone tissue engineering, and investigate the osteogenic differentiation of NELL1 gene-modified iPSC-MSCs seeded on Arg-Gly-Asp (RGD)-grafted calcium phosphate cement (CPC) scaffold. Cells were transduced with red fluorescence protein (RFP-iPSC-MSCs) or NELL1 (NELL1-iPSC-MSCs) by a lentiviral vector. Cell proliferation on RGD-grafted CPC scaffold, osteogenic differentiation and bone mineral synthesis were evaluated. RFP-iPSC-MSCs stably expressed high levels of RFP. Both the NELL1 gene and NELL1 protein levels were confirmed higher in NELL1-iPSC-MSCs than in RFP-iPSC-MSCs using RT-PCR and Western blot (P<0.05). Alkaline phosphatase activity was increased by 130% by NELL1 overexpression at 14days (P<0.05), indicating that NELL1 promoted iPSC-MSC osteogenic differentiation. When seeded on RGD-grafted CPC, NELL1-iPSC-MSCs attached and expanded similarly well to RFP-iPSC-MSCs. At 14days, the runt-related transcription factor 2 (RUNX2) gene level of NELL1-iPSC-MSCs was 2.0-fold that of RFP-iPSC-MSCs. The osteocalcin (OC) level of NELL1-iPSC-MSCs was 3.1-fold that of RFP-iPSC-MSCs (P<0.05). The collagen type I alpha 1 (COL1A1) gene level of NELL1-iPSC-MSCs was 1.7-fold that of RFP-iPSC-MSCs at 7days (P<0.05). Mineral synthesis was increased by 81% in NELL1-iPSC-MSCs at 21days. In conclusion, NELL1 overexpression greatly enhanced the osteogenic differentiation and mineral synthesis of iPSC-MSCs on RGD-grafted CPC scaffold for the first time. The novel NELL1-iPSC-MSC seeded RGD-CPC construct is promising for enhancing bone engineering.
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Bone tissue engineering via nanostructured calcium phosphate biomaterials and stem cells. Bone Res 2014; 2:14017. [PMID: 26273526 PMCID: PMC4472121 DOI: 10.1038/boneres.2014.17] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 07/25/2014] [Accepted: 07/29/2014] [Indexed: 02/05/2023] Open
Abstract
Tissue engineering is promising to meet the increasing need for bone regeneration. Nanostructured calcium phosphate (CaP) biomaterials/scaffolds are of special interest as they share chemical/crystallographic similarities to inorganic components of bone. Three applications of nano-CaP are discussed in this review: nanostructured calcium phosphate cement (CPC); nano-CaP composites; and nano-CaP coatings. The interactions between stem cells and nano-CaP are highlighted, including cell attachment, orientation/morphology, differentiation and in vivo bone regeneration. Several trends can be seen: (i) nano-CaP biomaterials support stem cell attachment/proliferation and induce osteogenic differentiation, in some cases even without osteogenic supplements; (ii) the influence of nano-CaP surface patterns on cell alignment is not prominent due to non-uniform distribution of nano-crystals; (iii) nano-CaP can achieve better bone regeneration than conventional CaP biomaterials; (iv) combining stem cells with nano-CaP accelerates bone regeneration, the effect of which can be further enhanced by growth factors; and (v) cell microencapsulation in nano-CaP scaffolds is promising for bone tissue engineering. These understandings would help researchers to further uncover the underlying mechanisms and interactions in nano-CaP stem cell constructs in vitro and in vivo, tailor nano-CaP composite construct design and stem cell type selection to enhance cell function and bone regeneration, and translate laboratory findings to clinical treatments.
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Li R, Wang C, Tong J, Su Y, Lin Y, Zhou X, Ye L. WNT6 promotes the migration and differentiation of human dental pulp cells partly through c-Jun N-terminal kinase signaling pathway. J Endod 2014; 40:943-8. [PMID: 24935540 DOI: 10.1016/j.joen.2013.12.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 12/03/2013] [Accepted: 12/17/2013] [Indexed: 01/09/2023]
Abstract
INTRODUCTION During the dental pulp repair process, human dental pulp cells (HDPCs) migrate to injury sites where they may differentiate into odontoblastlike cells. WNT6 plays a role in dental development and can activate a noncanonical pathway including the c-Jun N-terminal kinase (JNK) pathway. The mechanism of WNT6 in dental pulp repair is still unknown. The purpose of this study was to explore the potential role of the WNT6/JNK signaling pathway in the promotion of cell migration and the differentiation of HDPCs. METHODS The third passage of HDPCs were cultured in vitro and treated with WNT6 conditioned medium with or without the pretreatment of JNK inhibitor SP600125. The activation of JNK was detected by Western blot, the expression of c-Jun was quantified by reverse-transcription polymerase chain reaction, the migration of HDPCs was determined by wound healing and transwell migration assays, and the differentiation of HDPCs was investigated using alkaline phosphatase staining and alizarin red staining. The expression of odontogenesis-related genes such as Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein 1 was quantified. RESULTS WNT6 activates the JNK pathway in HDPCs and enhances cell migration, mineralization nodule formation, and alkaline phosphatase activation. WNT6 also increases the expression of Runt-related transcription factor 2, dentin sialophosphoprotein, and dentin matrix protein messenger RNA in HDPCs. Blockage of the JNK pathway in HDPCs decreases but does not completely abolish the cell migration and differentiation capacity induced by WNT6. CONCLUSIONS WNT6 activates the JNK signaling pathway in HDPCs, leading to migration and differentiation.
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Affiliation(s)
- Ruimin Li
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Juan Tong
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yingying Su
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
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