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1
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Xue P, Wang Y, Lv L, Wang D, Wang Y. Roles of Chemokines in Intervertebral Disk Degeneration. Curr Pain Headache Rep 2024; 28:95-108. [PMID: 37976014 DOI: 10.1007/s11916-023-01188-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE OF REVIEW Intervertebral disc degeneration is the primary etiology of low back pain and radicular pain. This review examines the roles of crucial chemokines in different stages of degenerative disc disease, along with interventions targeting chemokine function to mitigate disc degeneration. RECENT FINDINGS The release of chemokines from degenerated discs facilitates the infiltration and activation of immune cells, thereby intensifying the inflammatory cascade response. The migration of immune cells into the venous lumen is concomitant with the emergence of microvascular tissue and nerve fibers. Furthermore, the presence of neurogenic factors secreted by disc cells and immune cells stimulates the activation of pain-related cation channels in the dorsal root ganglion, potentially exacerbating discogenic and neurogenic pain and intensifying the degenerative cascade response mediated by chemokines. Gaining a deeper comprehension of the functions of chemokines and immune cells in these processes involving catabolism, angiogenesis, and injury detection could offer novel therapeutic avenues for managing symptomatic disc disease.
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Affiliation(s)
- Pengfei Xue
- Medical School of Southeast University, Nanjing, Jiangsu, 210009, China
- Central Laboratory, Gaochun Hospital Affiliated to Jiangsu University, Nanjing, Jiangsu, 211300, China
| | - Yi Wang
- Department of Orthopaedics, Jiujiang Traditional Chinese Medicine Hospital, Jiujiang, Jiangxi, 332000, China
| | - Long Lv
- Central Laboratory, Gaochun Hospital Affiliated to Jiangsu University, Nanjing, Jiangsu, 211300, China
| | - Dongming Wang
- Central Laboratory, Gaochun Hospital Affiliated to Jiangsu University, Nanjing, Jiangsu, 211300, China.
| | - Yuntao Wang
- Medical School of Southeast University, Nanjing, Jiangsu, 210009, China.
- Department of Spine Center, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China.
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2
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Shin S, Lee J, Kwon Y, Park KS, Jeong JH, Choi SJ, Bang SI, Chang JW, Lee C. Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose, Bone Marrow, Placenta and Wharton's Jelly. Int J Mol Sci 2021; 22:ijms22020845. [PMID: 33467726 PMCID: PMC7829982 DOI: 10.3390/ijms22020845] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have the potential to be a viable therapy against various diseases due to their paracrine effects, such as secretion of immunomodulatory, trophic and protective factors. These cells are known to be distributed within various organs and tissues. Although they possess the same characteristics, MSCs from different sources are believed to have different secretion potentials and patterns, which may influence their therapeutic effects in disease environments. We characterized the protein secretome of adipose (AD), bone marrow (BM), placenta (PL), and Wharton’s jelly (WJ)-derived human MSCs by using conditioned media and analyzing the secretome by mass spectrometry and follow-up bioinformatics. Each MSC secretome profile had distinct characteristics depending on the source. However, the functional analyses of the secretome from different sources showed that they share similar characteristics, such as cell migration and negative regulation of programmed cell death, even though differences in the composition of the secretome exist. This study shows that the secretome of fetal-derived MSCs, such as PL and WJ, had a more diverse composition than that of AD and BM-derived MSCs, and it was assumed that their therapeutic potential was greater because of these properties.
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Affiliation(s)
- Sungho Shin
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
| | - Jeongmin Lee
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea;
- R&D Center, ENCell Co., Ltd., Seoul 06351, Korea
| | - Yumi Kwon
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
| | - Kang-Sik Park
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Jae-Hoon Jeong
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;
| | - Suk-Joo Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Sa Ik Bang
- Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea;
- R&D Center, ENCell Co., Ltd., Seoul 06351, Korea
- Correspondence: (J.W.C.); (C.L.)
| | - Cheolju Lee
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
- Correspondence: (J.W.C.); (C.L.)
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3
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Nguyen T, Urrutia-Cabrera D, Liou RHC, Luu CD, Guymer R, Wong RCB. New Technologies to Study Functional Genomics of Age-Related Macular Degeneration. Front Cell Dev Biol 2021; 8:604220. [PMID: 33505962 PMCID: PMC7829507 DOI: 10.3389/fcell.2020.604220] [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: 09/09/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022] Open
Abstract
Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in people over 50 years old in developed countries. Currently, we still lack a comprehensive understanding of the genetic factors contributing to AMD, which is critical to identify effective therapeutic targets to improve treatment outcomes for AMD patients. Here we discuss the latest technologies that can facilitate the identification and functional study of putative genes in AMD pathology. We review improved genomic methods to identify novel AMD genes, advances in single cell transcriptomics to profile gene expression in specific retinal cell types, and summarize recent development of in vitro models for studying AMD using induced pluripotent stem cells, organoids and biomaterials, as well as new molecular technologies using CRISPR/Cas that could facilitate functional studies of AMD-associated genes.
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Affiliation(s)
- Tu Nguyen
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
| | - Daniel Urrutia-Cabrera
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
| | - Roxanne Hsiang-Chi Liou
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
| | - Chi D Luu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
| | - Robyn Guymer
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
| | - Raymond Ching-Bong Wong
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.,Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
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4
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Novoseletskaya E, Grigorieva O, Nimiritsky P, Basalova N, Eremichev R, Milovskaya I, Kulebyakin K, Kulebyakina M, Rodionov S, Omelyanenko N, Efimenko A. Mesenchymal Stromal Cell-Produced Components of Extracellular Matrix Potentiate Multipotent Stem Cell Response to Differentiation Stimuli. Front Cell Dev Biol 2020; 8:555378. [PMID: 33072743 PMCID: PMC7536557 DOI: 10.3389/fcell.2020.555378] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Extracellular matrix (ECM) provides both structural support and dynamic microenvironment for cells regulating their behavior and fate. As a critical component of stem cell niche ECM maintains stem cells and activates their proliferation and differentiation under specific stimuli. Mesenchymal stem/stromal cells (MSCs) regulate tissue-specific stem cell functions locating in their immediate microenvironment and producing various bioactive factors, including ECM components. We evaluated the ability of MSC-produced ECM to restore stem and progenitor cell microenvironment in vitro and analyzed the possible mechanisms of its effects. Human MSC cell sheets were decellularized by different agents (detergents, enzymes, and apoptosis inductors) to select the optimized combination (CHAPS and DNAse I) based on the conservation of decellularized ECM (dECM) structure and effectiveness of DNA removal. Prepared dECM was non-immunogenic, supported MSC proliferation and formation of larger colonies in colony-forming unit-assay. Decellularized ECM effectively promoted MSC trilineage differentiation (adipogenic, osteogenic, and chondrogenic) compared to plastic or plastic covered by selected ECM components (collagen, fibronectin, laminin). Interestingly, dECM produced by human fibroblasts could not enhance MSC differentiation like MSC-produced dECM, indicating cell-specific functionality of dECM. We demonstrated the significant integrin contribution in dECM-cell interaction by blocking the stimulatory effects of dECM with RGD peptide and suggested the involvement of key intracellular signaling pathways activation (pERK/ERK and pFAK/FAK axes, pYAP/YAP and beta-catenin) in the observed processes based on the results of inhibitory analysis. Taken together, we suppose that MSC-produced dECM may mimic stem cell niche components in vitro and maintain multipotent progenitor cells to insure their effective response to external differentiating stimuli upon activation. The obtained data provide more insights into the possible role of MSC-produced ECM in stem and progenitor cell regulation within their niches. Our results are also useful for the developing of dECM-based cell-free products for regenerative medicine.
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Affiliation(s)
- Ekaterina Novoseletskaya
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Olga Grigorieva
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia
| | - Peter Nimiritsky
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Nataliya Basalova
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Roman Eremichev
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia
| | - Irina Milovskaya
- Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Konstantin Kulebyakin
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Maria Kulebyakina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Sergei Rodionov
- N.N. Priorov National Medical Research Center of Traumatology and Orthopedics, Moscow, Russia
| | - Nikolai Omelyanenko
- N.N. Priorov National Medical Research Center of Traumatology and Orthopedics, Moscow, Russia
| | - Anastasia Efimenko
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
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5
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Yu Y, Cui H, Zhang C, Zhang D, Yin J, Wen G, Chai Y. Human nail bed extracellular matrix facilitates bone regeneration via macrophage polarization mediated by the JAK2/STAT3 pathway. J Mater Chem B 2020; 8:4067-4079. [PMID: 32242565 DOI: 10.1039/c9tb02910a] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Critical-sized bone defects caused by trauma, tumor resection or serious infection represent one of the most challenging problems faced by orthopedic surgeons. However, the construction of bone grafts with good osteointegration and osteoinductivity is a clinical challenge. It has been elaborated that the nail bed tissue is an essential element for digit tip regeneration, suggesting that the nail bed may serve as a new material to manipulate bone regeneration. Herein, it was found that human nail bed extracellular matrix derived from amputated patients stimulates macrophage polarization toward a pro-healing phenotype and the expression of BMP2, to facilitate the osteogenic differentiation of bone marrow stromal cells (BMSCs) in vitro. The in vivo osteogenic capacity of decellularized nail bed scaffolds was then confirmed using a rat model of critical-sized calvarial defects. The in-depth analysis of immune responses to implanted scaffolds revealed that macrophage polarization toward the pro-regenerative M2 phenotype directs osteogenesis, as confirmed by macrophage depletion. A combination of proteomics analysis and RNA interference verified that the JAK2/STAT3 pathway is the positive regulator of macrophage polarization initiated by the decellularized nail bed during the promoted osteogenesis process. Thus, the decellularized human nail bed scaffold developed in this work is a promising biomaterial for bone regeneration.
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Affiliation(s)
- Yaling Yu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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6
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Vangala G, Imhoff FM, Squires CM, Cridge AG, Baird SK. Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D. Exp Cell Res 2019; 383:111494. [DOI: 10.1016/j.yexcr.2019.07.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/13/2022]
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7
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Xu XH, Yuan TJ, Ye PW, Wang MZ, Ma HJ, Jiang ZH, Zhang YP, Peng LH. Construction of a biomimetic chemokine reservoir stimulates rapid in situ wound repair and regeneration. Int J Pharm 2019; 570:118648. [PMID: 31465833 DOI: 10.1016/j.ijpharm.2019.118648] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/07/2019] [Accepted: 08/25/2019] [Indexed: 12/17/2022]
Abstract
Skin is the first protection of human body. It is always challenged by a range of external factors, resulting in the wounds of skin. Hydrogel, as a dressing with multiple advantages, causes increasing interests or the applications in wound treatment. However, the function and importance of micro-environment of wound region are frequently neglected. In this study, we successfully developed a chemokine loaded biomimetic hydrogel as a functional reservoir to stimulate the rapid in situ recruitment of BMSCs for fast wound repair and regeneration. The biomimetic hydrogel was fabricated by using the Polyvinyl alcohol (PVA) combined with chitosan (CS) as the hybrid materials. The fabricated hydrogel possesses many features such as the porous structure, high swelling rate and moisture retention property. More importantly, the incorporated chemokine could be released with a sustained manner from the hydrogel and recruited the bone marrow mesenchymal stem cells (BMSCs) significantly both in vitro & in vivo. Moreover, the hydrogel was demonstrated to be highly biocompatible to the skin tissue without any side effect or irritation observed. Topical delivery of chemokine by the biomimetic PVA/CS hybrid material based hydrogel is demonstrated as a promising carrier to accelerate wound repair and regeneration without inducing scar formation and any other negative complications. The PVA/CS/SDF-1 hydrogel was shown a novel therapeutic system for wound therapy.
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Affiliation(s)
- Xue-Han Xu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Tie-Jun Yuan
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Pei-Wu Ye
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Mao-Ze Wang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Hui-Jian Ma
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China
| | - Zhi-Hong Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China
| | - Yong-Pin Zhang
- Guiyang University of Chinese Medicine, Guiyang, Guizhou, PR China.
| | - Li-Hua Peng
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China.
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8
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Popielarczyk TL, Huckle WR, Barrett JG. Human Bone Marrow-Derived Mesenchymal Stem Cells Home via the PI3K-Akt, MAPK, and Jak/Stat Signaling Pathways in Response to Platelet-Derived Growth Factor. Stem Cells Dev 2019; 28:1191-1202. [PMID: 31190615 DOI: 10.1089/scd.2019.0003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have great potential to improve clinical outcomes for many inflammatory and degenerative diseases either through intravenously delivered MSCs or through mobilization and migration of endogenous MSCs to injury sites, termed "stem cell homing." Stem cell homing involves the processes of attachment to and transmigration through endothelial cells lining the vasculature and migration through the tissue stroma to a site of injury or inflammation. Although the process of leukocyte transendothelial migration (TEM) is well understood, far less is known about stem cell homing. In this study, a transwell-based model was developed to monitor adherence and TEM of human MSCs in response to chemokine exposure. Specifically, transwell membranes lined with human synovial microvascular endothelial cells were partitioned from the tissue injury-mimetic site containing chemokine stromal cell-derived factor-1 (SDF-1). Two population subsets of MSCs were studied: migratory cells that initiated transmigration on the endothelial lining and nonmigratory cells. We hypothesized that cells would adhere to and migrate through the endothelial lining in response to SDF-1 exposure and that gene and protein expression changes would be observed between migratory and nonmigratory cells. We validated a vasculature model for MSC transmigration that showed increased expression of several genes and activation of proteins of the PI3K-Akt, MAPK, and Jak/Stat signaling pathways. These findings showed that MSC homing may be driven by activation of PDGFRA/PI3K/Akt, PDGFRA/MAPK/Grb2, and PDGFRA/Jak2/Stat signaling, as a result of SDF-1-stimulated endothelial cell production of platelet-derived growth factor. This model can be used to further investigate these key regulatory molecules toward the development of targeted therapies.
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Affiliation(s)
- Tracee L Popielarczyk
- Department of Large Animal Clinical Sciences, Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, Virginia
| | - William R Huckle
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
| | - Jennifer G Barrett
- Department of Large Animal Clinical Sciences, Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, Virginia
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9
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Truong DD, Kratz A, Park JG, Barrientos ES, Saini H, Nguyen T, Pockaj B, Mouneimne G, LaBaer J, Nikkhah M. A Human Organotypic Microfluidic Tumor Model Permits Investigation of the Interplay between Patient-Derived Fibroblasts and Breast Cancer Cells. Cancer Res 2019; 79:3139-3151. [PMID: 30992322 PMCID: PMC6664809 DOI: 10.1158/0008-5472.can-18-2293] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 12/11/2018] [Accepted: 04/11/2019] [Indexed: 12/21/2022]
Abstract
Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions are partly comprised of the cross-talk between tumor and stromal fibroblasts, but the key molecular mechanisms within the cross-talk that govern cancer invasion are still unclear. Here, we adapted our previously developed microfluidic device as a 3D in vitro organotypic model to mechanistically study tumor-stroma interactions by mimicking the spatial organization of the tumor microenvironment on a chip. We cocultured breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions, respectively, and combined functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma cross-talk on invasion. This led to the observation that cancer-associated fibroblasts (CAF) enhanced invasion in 3D by inducing expression of a novel gene of interest, glycoprotein nonmetastatic B (GPNMB), in breast cancer cells, resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAF on enhanced cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient-specific tumor microenvironments to investigate the cellular and molecular consequences of tumor-stroma interactions. SIGNIFICANCE: An organotypic model of tumor-stroma interactions on a microfluidic chip reveals that CAFs promote invasion by enhancing expression of GPNMB in breast cancer cells.
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Affiliation(s)
- Danh D Truong
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona
| | - Alexander Kratz
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona
| | - Jin G Park
- Virginia G. Piper Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Eric S Barrientos
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona
| | - Harpinder Saini
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona
| | - Toan Nguyen
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona
| | | | | | - Joshua LaBaer
- Virginia G. Piper Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Mehdi Nikkhah
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona.
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10
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Clouet J, Fusellier M, Camus A, Le Visage C, Guicheux J. Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Adv Drug Deliv Rev 2019; 146:306-324. [PMID: 29705378 DOI: 10.1016/j.addr.2018.04.017] [Citation(s) in RCA: 145] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/24/2018] [Indexed: 12/15/2022]
Abstract
Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process. Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.
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Affiliation(s)
- Johann Clouet
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; CHU Nantes, Pharmacie Centrale, PHU 11, Nantes F-44093, France; Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, Nantes F-44035, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Marion Fusellier
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Department of Diagnostic Imaging, CRIP, National Veterinary School (ONIRIS), Nantes F-44307, France
| | - Anne Camus
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Catherine Le Visage
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Jérôme Guicheux
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France; CHU Nantes, PHU4 OTONN, Nantes, F-44093, France.
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11
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Robb KP, Shridhar A, Flynn LE. Decellularized Matrices As Cell-Instructive Scaffolds to Guide Tissue-Specific Regeneration. ACS Biomater Sci Eng 2017; 4:3627-3643. [PMID: 33429606 DOI: 10.1021/acsbiomaterials.7b00619] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Decellularized scaffolds are promising clinically translational biomaterials that can be applied to direct cell responses and promote tissue regeneration. Bioscaffolds derived from the extracellular matrix (ECM) of decellularized tissues can naturally mimic the complex extracellular microenvironment through the retention of compositional, biomechanical, and structural properties specific to the native ECM. Increasingly, studies have investigated the use of ECM-derived scaffolds as instructive substrates to recapitulate properties of the stem cell niche and guide cell proliferation, paracrine factor production, and differentiation in a tissue-specific manner. Here, we review the application of decellularized tissue scaffolds as instructive matrices for stem or progenitor cells, with a focus on the mechanisms through which ECM-derived scaffolds can mediate cell behavior to promote tissue-specific regeneration. We conclude that although additional preclinical studies are required, ECM-derived scaffolds are a promising platform to guide cell behavior and may have widespread clinical applications in the field of regenerative medicine.
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Affiliation(s)
- Kevin P Robb
- Biomedical Engineering Graduate Program, The University of Western Ontario, Claudette MacKay Lassonde Pavilion, London, Ontario, Canada N6A 5B9
| | - Arthi Shridhar
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, Thompson Engineering Building, London, Ontario, Canada N6A 5B9
| | - Lauren E Flynn
- Department of Chemical and Biochemical Engineering, The University of Western Ontario, Thompson Engineering Building, London, Ontario, Canada N6A 5B9.,Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1
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12
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Chen G, Lv Y. Matrix elasticity-modified scaffold loaded with SDF-1α improves the in situ regeneration of segmental bone defect in rabbit radius. Sci Rep 2017; 7:1672. [PMID: 28490814 PMCID: PMC5432001 DOI: 10.1038/s41598-017-01938-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/05/2017] [Indexed: 12/20/2022] Open
Abstract
The effectiveness of stem-cell based therapy has been hampered by the limited availability of stem cell sources, immune rejection, and difficulties in clinical adoption and regulatory approval. These obstacles can be partially circumvented by using in situ tissue engineering that recruits the endogenous stem/progenitor cells and provides cues to direct stem cell phenotype. Here, decellularized bone scaffold is mechanically modified by coating of collagen (Col)/hydroxyapatite (HA) mixture with optimal ratio and loaded with chemokine stromal cell-derived factor-1α (SDF-1α), in which endogenous stem cell recruitment can be improved by chemokine and stem cell fate can be regulated by matrix elasticity of the scaffold. This study shows that mesenchymal stem cells (MSCs) osteogenesis in vitro was enhanced by matrix elasticity and SDF-1α, and endogenous MSCs recruitment in subcutaneous implantation of rat was increased by the release of SDF-1α from the scaffold, and bone regeneration in rabbit large bone defect model was significantly improved by matrix elasticity and SDF-1α. In short, this study provides a new insight for developing novel engineered cell-free bone substitutes by mechanical modification for tissue engineering and regenerative medicine.
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Affiliation(s)
- Guobao Chen
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, P. R. China
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, P. R. China
| | - Yonggang Lv
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, P. R. China.
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, P. R. China.
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13
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Abstract
Mesenchymal stem cells (MSCs) have great potential as a source of cells for cell-based therapy because of their ability for self-renewal and differentiation into functional cells. Moreover, matrix metalloproteinases (MMPs) have a critical role in the differentiation of MSCs into different lineages. MSCs also interact with exogenous MMPs at their surface, and regulate the pericellular localization of MMP activities. The fate of MSCs is regulated by specific MMPs associated with a key cell lineage. Recent reports suggest the integration of MMPs in the differentiation, angiogenesis, proliferation, and migration of MSCs. These interactions are not fully understood and warrant further investigation, especially for their application as therapeutic tools to treat different diseases. Therefore, overexpression of a single MMP or tissue-specific inhibitor of metalloproteinase in MSCs may promote transdifferentiation into a specific cell lineage, which can be used for the treatment of some diseases. In this review, we critically discuss the identification of various MMPs and the signaling pathways that affect the differentiation, migration, angiogenesis, and proliferation of MSCs.
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Affiliation(s)
- Sami G Almalki
- Department of Clinical and Translational Science, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE, 68178, USA
| | - Devendra K Agrawal
- Department of Clinical and Translational Science, Creighton University School of Medicine, CRISS II, Room 510, 2500 California Plaza, Omaha, NE, 68178, USA.
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14
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Abstract
Biomaterials have played an increasingly prominent role in the success of biomedical devices and in the development of tissue engineering, which seeks to unlock the regenerative potential innate to human tissues/organs in a state of deterioration and to restore or reestablish normal bodily function. Advances in our understanding of regenerative biomaterials and their roles in new tissue formation can potentially open a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multi-component construction of native extracellular matrices (ECMs) for cell accommodation, the synthetic biomaterials produced today routinely incorporate biologically active components to define an artificial in vivo milieu with complex and dynamic interactions that foster and regulate stem cells, similar to the events occurring in a natural cellular microenvironment. The range and degree of biomaterial sophistication have also dramatically increased as more knowledge has accumulated through materials science, matrix biology and tissue engineering. However, achieving clinical translation and commercial success requires regenerative biomaterials to be not only efficacious and safe but also cost-effective and convenient for use and production. Utilizing biomaterials of human origin as building blocks for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural tissue with regard to its physical and chemical properties for the orchestration of wound healing and tissue regeneration. In addition to directly using tissue transfers and transplants for repair, new applications of human-derived biomaterials are now focusing on the use of naturally occurring biomacromolecules, decellularized ECM scaffolds and autologous preparations rich in growth factors/non-expanded stem cells to either target acceleration/magnification of the body's own repair capacity or use nature's paradigms to create new tissues for restoration. In particular, there is increasing interest in separating ECMs into simplified functional domains and/or biopolymeric assemblies so that these components/constituents can be discretely exploited and manipulated for the production of bioscaffolds and new biomimetic biomaterials. Here, following an overview of tissue auto-/allo-transplantation, we discuss the recent trends and advances as well as the challenges and future directions in the evolution and application of human-derived biomaterials for reconstructive surgery and tissue engineering. In particular, we focus on an exploration of the structural, mechanical, biochemical and biological information present in native human tissue for bioengineering applications and to provide inspiration for the design of future biomaterials.
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15
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Swinehart IT, Badylak SF. Extracellular matrix bioscaffolds in tissue remodeling and morphogenesis. Dev Dyn 2016; 245:351-60. [PMID: 26699796 DOI: 10.1002/dvdy.24379] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/10/2015] [Accepted: 12/14/2015] [Indexed: 12/13/2022] Open
Abstract
During normal morphogenesis the extracellular matrix (ECM) influences cell motility, proliferation, apoptosis, and differentiation. Tissue engineers have attempted to harness the cell signaling potential of ECM to promote the functional reconstruction, if not regeneration, of injured or missing adult tissues that otherwise heal by the formation of scar tissue. ECM bioscaffolds, derived from decellularized tissues, have been used to promote the formation of site appropriate, functional tissues in many clinical applications including skeletal muscle, fibrocartilage, lower urinary tract, and esophageal reconstruction, among others. These scaffolds function by the release or exposure of growth factors and cryptic peptides, modulation of the immune response, and recruitment of progenitor cells. Herein, we describe this process of ECM induced constructive remodeling and examine similarities to normal tissue morphogenesis.
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Affiliation(s)
- Ilea T Swinehart
- McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.,Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania
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16
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Friedrich U, Datta S, Schubert T, Plössl K, Schneider M, Grassmann F, Fuchshofer R, Tiefenbach KJ, Längst G, Weber BHF. Synonymous variants in HTRA1 implicated in AMD susceptibility impair its capacity to regulate TGF-β signaling. Hum Mol Genet 2015; 24:6361-73. [PMID: 26310622 DOI: 10.1093/hmg/ddv346] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/19/2015] [Indexed: 12/16/2023] Open
Abstract
High-temperature requirement A1 (HTRA1) is a secreted serine protease reported to play a role in the development of several cancers and neurodegenerative diseases. Still, the mechanism underlying the disease processes largely remains undetermined. In age-related macular degeneration (AMD), a common cause of vision impairment and blindness in industrialized societies, two synonymous polymorphisms (rs1049331:C>T, and rs2293870:G>T) in exon 1 of the HTRA1 gene were associated with a high risk to develop disease. Here, we show that the two polymorphisms result in a protein with altered thermophoretic properties upon heat-induced unfolding, trypsin accessibility and secretion behavior, suggesting unique structural features of the AMD-risk-associated HTRA1 protein. Applying MicroScale Thermophoresis and protease digestion analysis, we demonstrate direct binding and proteolysis of transforming growth factor β1 (TGF-β1) by normal HTRA1 but not the AMD-risk-associated isoform. As a consequence, both HTRA1 isoforms strongly differed in their ability to control TGF-β mediated signaling, as revealed by reporter assays targeting the TGF-β1-induced serpin peptidase inhibitor (SERPINE1, alias PAI-1) promoter. In addition, structurally altered HTRA1 led to an impaired autocrine TGF-β signaling in microglia, as measured by a strong down-regulation of downstream effectors of the TGF-β cascade such as phosphorylated SMAD2 and PAI-1 expression. Taken together, our findings demonstrate the effects of two synonymous HTRA1 variants on protein structure and protein interaction with TGF-β1. As a consequence, this leads to an impairment of TGF-β signaling and microglial regulation. Functional implications of the altered properties on AMD pathogenesis remain to be clarified.
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Affiliation(s)
- Ulrike Friedrich
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Shyamtanu Datta
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Thomas Schubert
- Department of Biochemistry, University of Regensburg, 2bind GmbH, Josef Engert Straße 13, 93053 Regensburg, Germany
| | - Karolina Plössl
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | | | - Felix Grassmann
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | | | - Klaus-Jürgen Tiefenbach
- Institute of Biophysics and Physical Biochemistry, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany and
| | - Gernot Längst
- Department of Biochemistry, University of Regensburg
| | - Bernhard H F Weber
- Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany,
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17
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Li CJ, Madhu V, Balian G, Dighe AS, Cui Q. Cross-Talk Between VEGF and BMP-6 Pathways Accelerates Osteogenic Differentiation of Human Adipose-Derived Stem Cells. J Cell Physiol 2015; 230:2671-82. [PMID: 25753222 DOI: 10.1002/jcp.24983] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 03/03/2015] [Indexed: 12/29/2022]
Abstract
Deficiency in vascular endothelial growth factor (VEGF) or bone morphogenetic proteins (BMPs) results in fracture non-unions. Therefore, it is indispensable to comprehend the combined effect of VEGF and BMPs on the osteogenic differentiation of osteoprogenitor mesenchymal stem cells (MSCs) that are either naturally occurring at the fracture repair site or exogenously added to enhance the bone repair. We found that the combination of VEGF and BMP-6 enhanced COL1A2 expression, which correlated with upregulated expression of osterix, Dlx5, and Msx2 in human adipose-derived stem cells (hADSCs). Cross-talk between VEGF and BMP-6 pathways upregulated activation of p38 mitogen-activated kinase (p38 MAPK) and inhibited activation of protein kinase B (PKB, also known as Akt), whereas phosphorylation of "mothers against decapentaplegic" homologs 1/5/8 (Smads 1/5/8) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) was not affected. Consistent with these findings, p38 inhibitor SB203580, or siRNA knockdown of osterix, abrogated crosstalk between the VEGF and BMP-6 pathways and significantly reduced the observed upregulation of COL1A2. Nuclear translocation of the phosphorylated form of osterix was also inhibited by SB203580. Although crosstalk between the VEGF-BMP-6 pathways did not show an effect on the extent of mineralization, inhibition of any one of the three components that were upregulated through the cross-talk, i.e., osterix, Dlx5, and p38 activation, led to a complete inhibition of mineralization. Inhibition of PKB/Akt activation, which is attenuated through the cross-talk, significantly enhanced ALP gene expression. These observations imply that crosstalk between the VEGF and BMP-6 signaling pathways enhances osteogenic differentiation of MSCs.
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Affiliation(s)
- Ching-Ju Li
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia
| | - Vedavathi Madhu
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia
| | - Gary Balian
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia
| | - Abhijit S Dighe
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia
| | - Quanjun Cui
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia
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18
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Maguire G, Friedman P. Systems biology approach to developing S 2RM-based “systems therapeutics” and naturally induced pluripotent stem cells. World J Stem Cells 2015; 7:745-756. [PMID: 26029345 PMCID: PMC4444614 DOI: 10.4252/wjsc.v7.i4.745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/25/2014] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell’s power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely “systems therapeutic”, can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called “systems therapeutics”. A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S2RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S2RM technology, to develop a new class of therapeutics called “systems therapeutics.” Given the ubiquitous and powerful nature of innate S2RM-based healing in the human body, this “systems therapeutic” approach using S2RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.
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19
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Improvement of cytocompatibility of polylactide by filling with marine algae powder. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2015; 50:309-16. [PMID: 25746275 DOI: 10.1016/j.msec.2015.02.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 01/11/2015] [Accepted: 02/09/2015] [Indexed: 11/21/2022]
Abstract
This work evaluated the cytocompatibility, thermal and mechanical properties of composites of polylactide (PLA) and marine algae powder (MAP). To improve the thermal and mechanical properties of PLA-MAP composites, glycidyl methacrylate (GMA) was used as the compatibilizer for the blending of PLA and MAP. The PLA-g-GMA/MAP composites exhibited superior mechanical properties, attributing to higher compatibility between the polymer and MAP, comparing to PLA/MAP composites. The dispersion of MAP in the PLA-g-GMA matrix was highly homogeneous as a result of etherification. The lower melt torque of the PLA-g-GMA/MAP composites also made them more processable than PLA/MAP. To assess the cytocompatibility, normal human foreskin fibroblasts (FBs) were seeded onto each type of the composites. Results of FB proliferation, collagen production, and cytotoxicity assays indicated greater cytocompatibility for the PLA/MAP composites than for the PLA-g-GMA/MAP composites. Furthermore, both PLA/MAP and PLA-g-GMA/MAP composites were more cytocompatible than pure PLA.
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20
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Chan TM, Lin HP, Lin SZ. In situ altering of the extracellular matrix to direct the programming of endogenous stem cells. Stem Cells 2015; 32:1989-90. [PMID: 24590489 DOI: 10.1002/stem.1693] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 01/18/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Tzu-Min Chan
- Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, Republic of China; Everfront Biotech, Inc., New Taipei City, Taiwan, Republic of China
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21
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Kim SH, Hur W, Kim JE, Min HJ, Kim S, Min HS, Kim BK, Kim SH, Choi TH, Jung Y. Self-assembling peptide nanofibers coupled with neuropeptide substance P for bone tissue engineering. Tissue Eng Part A 2015; 21:1237-46. [PMID: 25411965 DOI: 10.1089/ten.tea.2014.0472] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The number of patients requiring flat bone transplantation continues to increase worldwide. Cell transplantation has been successfully applied clinically; however, it causes another defect site and the time requirements to harvest cells and expand them are considerable. In this study, KLD12/KLD12-SP (KLD12+KLD12-substance P [SP]) was designed to mimic endogenous tissue-healing processes. The structures of KLD12, KLD12-SP, and KLD12/KLD12-SP were observed by transmission electron microscopy and circular dichroism spectra. KLD12/KLD12-SP nanofibers (5-10 nm) were created under physiological conditions by formation of a β-sheet structure. The ability of mesenchymal stem cells (MSCs) to recruit KLD12/KLD12-SP was observed by using an in vivo fluorescence imaging system. Labeled human bone marrow stromal cells supplied via an intravenous injection were recruited to the scaffold containing KLD12/KLD12-SP. Polylactic acid/beta-tricalcium phosphate (PLA/β-TCP) scaffolds filled with KLD12/KLD12-SP were applied to repair calvarial defects. The composite constructs (groups: defect, PLA/β-TCP, PLA/β-TCP/KLD12, and PLA/β-TCP/KLD12/KLD12-SP) were implanted into rat defect sites. Bone tissue regeneration was evaluated by observing gross morphology by hematoxylin and eosin and Masson's trichrome staining at 12 and 24 weeks after surgery. Gross morphology showed that the defect site was filled with new tissue that was integrated with host tissue in the KLD12/KLD12-SP group. In addition, from the staining data, cells were recruited to the defect site and lacunae structures formed in the KLD12/KLD12-SP group. From these results, the PLA/β-TCP+KLD12/KLD12-SP composite construct was considered for enhancement of bone tissue regeneration without cell transplantation.
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Affiliation(s)
- Su Hee Kim
- 1 Center for Biomaterials, Biomedical Research Institute , Korea Institute of Science and Technology, Seoul, Korea
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22
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Wang JY, Liou A, Ren ZH, Zhang L, Brown BN, Cui XT, Badylak SF, Cai YN, Guan YQ, Leak RK, Chen J, Ji X, Chen L. Neurorestorative effect of urinary bladder matrix-mediated neural stem cell transplantation following traumatic brain injury in rats. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2014; 12:413-425. [PMID: 23469853 DOI: 10.2174/1871527311312030014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 11/01/2012] [Accepted: 11/11/2012] [Indexed: 12/18/2022]
Abstract
Traumatic brain injury (TBI) is a leading cause of cell death and disability among young adults and lacks a successful therapeutic strategy. The multiphasic injuries of TBI severely limit the success of conventional pharmacological approaches. Recent successes with transplantation of stem cells in bioactive scaffolds in other injury paradigms provide new hope for the treatment of TBI. In this study, we transplanted neural stem cells (0.5x10(5) cells/µl) cultured in a bioactive scaffold derived from porcine urinary bladder matrix (UBM; 4 injection sites, 2.5µl each) into the rat brain following controlled cortical impact (CCI, velocity, 4.0 m/sec; duration, 0.5 sec; depth, 3.2mm). We evaluated the effectiveness of this strategy to combat the loss of motor, memory and cognitive faculties. Before transplantation, compatibility experiments showed that UBM was able to support extended proliferation and differentiation of neural stem cells. Together with its reported anti-inflammatory properties and rapid degradation characteristics in vivo, UBM emerged to be an ideal scaffold. The transplants reduced neuron/tissue loss and white matter injury, and also significantly ameliorated motor, memory, and cognitive impairments. Furthermore, exposure to UBM alone was sufficient to decrease the loss of sensorimotor skills from TBI (examined 3-28 days post-CCI). However, only UBMs that contained proliferating neural stem cells helped attenuate memory and cognitive impairments (examined 26-28 days post-CCI). In summary, these results demonstrate the therapeutic efficacy of stem cells in bioactive scaffolds against TBI and show promise for translation into future clinical use.
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Affiliation(s)
- J Y Wang
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Akf Liou
- Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Z H Ren
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - L Zhang
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - B N Brown
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA 15261, USA.,Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - X T Cui
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA 15261, USA.,Center for Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - S F Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA 15261, USA.,Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Y N Cai
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Y Q Guan
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Rehana K Leak
- Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, U.S.A
| | - J Chen
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China.,Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - X Ji
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - L Chen
- Department of Neurosurgery and China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, China
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23
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Ullah M, Sittinger M, Ringe J. Extracellular matrix of adipogenically differentiated mesenchymal stem cells reveals a network of collagen filaments, mostly interwoven by hexagonal structural units. Matrix Biol 2013; 32:452-465. [PMID: 23851162 DOI: 10.1016/j.matbio.2013.07.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 07/02/2013] [Accepted: 07/04/2013] [Indexed: 12/24/2022]
Abstract
Extracellular matrix (ECM) is the non-cellular component of tissues, which not only provides biological shelter but also takes part in the cellular decisions for diverse functions. Every tissue has an ECM with unique composition and topology that governs the process of determination, differentiation, proliferation, migration and regeneration of cells. Little is known about the structural organization of matrix especially of MSC-derived adipogenic ECM. Here, we particularly focus on the composition and architecture of the fat ECM to understand the cellular behavior on functional bases. Thus, mesenchymal stem cells (MSC) were adipogenically differentiated, then, were transferred to adipogenic propagation medium, whereas they started the release of lipid droplets leaving bare network of ECM. Microarray analysis was performed, to indentify the molecular machinery of matrix. Adipogenesis was verified by Oil Red O staining of lipid droplets and by qPCR of adipogenic marker genes PPARG and FABP4. Antibody staining demonstrated the presence of collagen type I, II and IV filaments, while alkaline phosphatase activity verified the ossified nature of these filaments. In the adipogenic matrix, the hexagonal structures were abundant followed by octagonal structures, whereas they interwoven in a crisscross manner. Regarding molecular machinery of adipogenic ECM, the bioinformatics analysis revealed the upregulated expression of COL4A1, ITGA7, ITGA7, SDC2, ICAM3, ADAMTS9, TIMP4, GPC1, GPC4 and downregulated expression of COL14A1, ADAMTS5, TIMP2, TIMP3, BGN, LAMA3, ITGA2, ITGA4, ITGB1, ITGB8, CLDN11. Moreover, genes associated with integrins, glycoproteins, laminins, fibronectins, cadherins, selectins and linked signaling pathways were found. Knowledge of the interactive-language between cells and matrix could be beneficial for the artificial designing of biomaterials and bioscaffolds.
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Affiliation(s)
- Mujib Ullah
- Tissue Engineering Laboratory & Berlin-Brandenburg Center for Regenerative Therapies, Dept. of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany.
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24
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Volloch V, Olsen BR. Why cellular stress suppresses adipogenesis in skeletal tissue, but is ineffective in adipose tissue: control of mesenchymal cell differentiation via integrin binding sites in extracellular matrices. Matrix Biol 2013; 32:365-71. [PMID: 23792045 DOI: 10.1016/j.matbio.2013.06.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 05/13/2013] [Accepted: 05/14/2013] [Indexed: 01/16/2023]
Abstract
This Perspective addresses one of the major puzzles of adipogenesis in adipose tissue, namely its resistance to cellular stress. It introduces a concept of "density" of integrin binding sites in extracellular matrix, proposes a cellular signaling explanation for the observed effects of matrix elasticity and of cell shape on mesenchymal stem cell differentiation, and discusses how specialized integrin binding sites in collagen IV-containing matrices guard two pivotal physiological and evolutionary processes: stress-resistant adipogenesis in adipose tissues and preservation of pluripotency of mesenchymal stem-like cells in their storage niches. Finally, it proposes strategies to suppress adipogenesis in adipose tissues.
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Affiliation(s)
- Vladimir Volloch
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
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25
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Hoareau L, Bencharif K, Girard AC, Gence L, Delarue P, Hulard O, Festy F, Roche R. Effect of centrifugation and washing on adipose graft viability: A new method to improve graft efficiency. J Plast Reconstr Aesthet Surg 2013; 66:712-9. [DOI: 10.1016/j.bjps.2012.12.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 12/20/2012] [Accepted: 12/23/2012] [Indexed: 11/30/2022]
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26
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Jacobo SMP, DeAngelis MM, Kim IK, Kazlauskas A. Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1. Mol Cell Biol 2013; 33:1976-90. [PMID: 23478260 PMCID: PMC3647976 DOI: 10.1128/mcb.01283-12] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 02/27/2013] [Indexed: 11/20/2022] Open
Abstract
Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.
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Affiliation(s)
- Sarah Melissa P. Jacobo
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - Margaret M. DeAngelis
- Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
| | - Ivana K. Kim
- Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - Andrius Kazlauskas
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
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27
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Lehner A, Magdolen V, Schuster T, Kotzsch M, Kiechle M, Meindl A, Sweep FCGJ, Span PN, Gross E. Downregulation of serine protease HTRA1 is associated with poor survival in breast cancer. PLoS One 2013; 8:e60359. [PMID: 23580433 PMCID: PMC3620283 DOI: 10.1371/journal.pone.0060359] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 02/26/2013] [Indexed: 11/24/2022] Open
Abstract
HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p = 0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR = 0.45 [CI 0.23-0.90], p = 0.023; HR = 0.55 [CI 0.32-0.94], p = 0.028, respectively), with even more pronounced impact in node-positive patients (HR = 0.21 [CI 0.07-0.63], p = 0.006; HR = 0.29 [CI 0.13-0.65], p = 0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n = 2809): HR = 0.79 [CI 0.7-0.9], log-rank p = 0.0003; for OS (n = 971): HR = 0.63 [CI 0.48-0.83], log-rank p = 0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.
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Affiliation(s)
- Anna Lehner
- Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany
| | - Viktor Magdolen
- Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany
| | - Tibor Schuster
- Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany
| | - Matthias Kotzsch
- Institute of Pathology, Dresden University of Technology, Dresden, Germany
| | - Marion Kiechle
- Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany
| | - Alfons Meindl
- Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany
| | - Fred C. G. J. Sweep
- Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Paul N. Span
- Department of Radiation Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Eva Gross
- Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany
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28
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Molecular characteristics of bone marrow mesenchymal stem cells, source of regenerative medicine. Int J Cardiol 2013; 163:125-31. [DOI: 10.1016/j.ijcard.2011.11.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 11/03/2011] [Accepted: 11/04/2011] [Indexed: 12/22/2022]
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29
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Sivakamasundari V, Lufkin T. Stemming the Degeneration: IVD Stem Cells and Stem Cell Regenerative Therapy for Degenerative Disc Disease. ACTA ACUST UNITED AC 2013; 2013. [PMID: 23951558 DOI: 10.5171/2013.724547] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The intervertebral disc (IVD) is immensely important for the integrity of vertebral column function. The highly specialized IVD functions to confer flexibility and tensile strength to the spine and endures various types of biomechanical force. Degenerative disc disease (DDD) is a prevalent musculoskeletal disorder and is the major cause of low back pain and includes the more severe degenerative lumbar scoliosis, disc herniation and spinal stenosis. DDD is a multifactorial disorder whereby an imbalance of anabolic and catabolic factors, or alterations to cellular composition, or biophysical stimuli and genetic background can all play a role in its genesis. However, our comprehension of IVD formation and theetiology of disc degeneration (DD) are far from being complete, hampering efforts to formulate appropriate therapies to tackle DD. Knowledge of the stem cells and various techniques to manipulate and direct them to particular fates have been promising in adopting a stem-cell based regenerative approach to DD. Moreover, new evidence on the residence of stem/progenitor cells within particular IVD niches has emerged holding promise for future therapeutic applications. Existing issues pertaining to current therapeutic approaches are also covered in this review.
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Pourrajab F, Forouzannia SK, Tabatabaee SA. WITHDRAWN: Molecular Characteristics of Bone Marrow Mesenchymal Stem Cells: An Appealing Source for Regenerative Medicine. Heart Lung Circ 2012:S1443-9506(12)00258-2. [PMID: 22939816 DOI: 10.1016/j.hlc.2012.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2011] [Revised: 10/08/2011] [Accepted: 04/26/2012] [Indexed: 11/18/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.hlc.2012.04.021. The duplicate article has therefore been withdrawn.
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Affiliation(s)
- Fatemeh Pourrajab
- Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Clinical Biochemistry, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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31
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Directed Fusion of Mesenchymal Stem Cells with Cardiomyocytes via VSV-G Facilitates Stem Cell Programming. Stem Cells Int 2012; 2012:414038. [PMID: 22701126 PMCID: PMC3369562 DOI: 10.1155/2012/414038] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Accepted: 02/22/2012] [Indexed: 01/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) spontaneously fuse with somatic cells in vivo, albeit rarely, and the fusion products are capable of tissue-specific function (mature trait) or proliferation (immature trait), depending on the microenvironment. That stem cells can be programmed, or somatic cells reprogrammed, in this fashion suggests that stem cell fusion holds promise as a therapeutic approach for the repair of damaged tissues, especially tissues not readily capable of functional regeneration, such as the myocardium. In an attempt to increase the frequency of stem cell fusion and, in so doing, increase the potential for cardiac tissue repair, we expressed the fusogen of the vesicular stomatitis virus (VSV-G) in human MSCs. We found VSV-G expressing MSCs (vMSCs) fused with cardiomyocytes (CMs) and these fusion products adopted a CM-like phenotype and morphology in vitro. In vivo, vMSCs delivered to damaged mouse myocardium via a collagen patch were able to home to the myocardium and fuse to cells within the infarct and peri-infarct region of the myocardium. This study provides a basis for the investigation of the biological impact of fusion of stem cells with CMs in vivo and illustrates how viral fusion proteins might better enable such studies.
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32
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Zhang L, Yuan T, Guo L, Zhang X. An in vitro study of collagen hydrogel to induce the chondrogenic differentiation of mesenchymal stem cells. J Biomed Mater Res A 2012; 100:2717-25. [PMID: 22623365 DOI: 10.1002/jbm.a.34194] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 03/17/2012] [Accepted: 03/26/2012] [Indexed: 02/04/2023]
Abstract
It is controversial whether a biomaterial itself, rather than addition of any exogenous growth factor, could induce mesenchymal stem cells (MSCs) to differentiate into chondrogenic lineage, further to regenerate cartilage. Previous studies have shown that collagen-based hydrogel could induce MSCs to differentiate into chondrocytes in vivo but the in vitro studies only have a few reports. The evidence that biomaterials could induce chondrogenesis is not adequate. In this study, we tried to address whether type I collagen hydrogel has chondro-inductive capability in vitro and how this scaffold induces MSCs to generate cartilage tissue without exogenous growth factors in the culture medium. We encapsulated neonatal rabbit bone marrow mesenchymal stem cells (BMSCs) in type I collagen hydrogel homogeneously or implanted cell aggregates in hydrogel, and cultured them in nonchondrogenic inductive media. After at least 28 days culture, cells in the homogeneous group were tending to chondrogenic differentiation while cell density was high, and cells in the aggregate group have almost gone through chondrogenesis and formed neo-cartilage tissue with abundant specific extracellular matrix (ECM) deposition. These results indicate collagen hydrogel has inherent inductivity for the chondrogenic differentiation of BMSCs, and the optimum specification and tissue formation were accompanied with local high cell density. This research suggests a feasible strategy to induce the chondro differentiation of BMSCs independent of exogenous growth factors, which may greatly contribute to clinical cartilage regeneration.
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Affiliation(s)
- Li Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, China
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33
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Exploiting extracellular matrix-stem cell interactions: A review of natural materials for therapeutic muscle regeneration. Biomaterials 2012; 33:428-43. [DOI: 10.1016/j.biomaterials.2011.09.078] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 09/28/2011] [Indexed: 02/07/2023]
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34
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Peng LH, Tsang SY, Tabata Y, Gao JQ. Genetically-manipulated adult stem cells as therapeutic agents and gene delivery vehicle for wound repair and regeneration. J Control Release 2011; 157:321-30. [PMID: 21893122 DOI: 10.1016/j.jconrel.2011.08.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 08/10/2011] [Indexed: 02/06/2023]
Abstract
Wound therapy remains a clinical challenge and much effort has been focused on the development of novel therapeutic approaches for wound management. New knowledge about the way in which signals control wound cellular and molecular behavior has promoted the topical application of multipotent stem cells and bioactive molecules to injured tissue, for skin regeneration with less scar formation. However, limited clinical success indicates that the effective delivery of polypeptides and therapeutic cells, with controlled releasing profile, is a major challenge which is yet to be overcome. Recently, a technique in which the genetically-manipulated stem cells were used both as the therapeutic agents and the vehicle for gene delivery for wound treatment - a method which serves to provide regenerative cells and bioactive genes within an optimal environment of regulatory molecular expression for wound sites - has emerged as a promising strategy for wound regenerative therapy. In this article, the roles of adult stem cells - as the therapeutics and the vehicles in these advanced biomimetic drug delivery systems for wound regeneration medicine - are scrutinized to indicate their mechanisms, characteristics, broad applicability and future lines of investigation.
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Affiliation(s)
- Li-Hua Peng
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, PR China
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35
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Starossom SC, Imitola J, Wang Y, Cao L, Khoury SJ. Subventricular zone microglia transcriptional networks. Brain Behav Immun 2011; 25:991-9. [PMID: 21074605 PMCID: PMC3109092 DOI: 10.1016/j.bbi.2010.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2010] [Revised: 11/03/2010] [Accepted: 11/03/2010] [Indexed: 01/19/2023] Open
Abstract
Microglia play an important role in inflammatory diseases of the central nervous system. There is evidence of microglial diversity with distinct phenotypes exhibiting either neuroprotection and repair or neurotoxicity. However the precise molecular mechanisms underlying this diversity are still unknown. Using a model of experimental autoimmune encephalomyelitis (EAE) we performed transcriptional profiling of isolated subventricular zone microglia from the acute and chronic disease phases of EAE. We found that microglia exhibit disease phase specific gene expression signatures, that correspond to unique gene ontology functions and genomic networks. Our data demonstrate for the first time, distinct transcriptional networks of microglia activation in vivo, that suggests a role as mediators of injury or repair.
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Affiliation(s)
- Sarah C. Starossom
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Jaime Imitola
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Yue Wang
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Li Cao
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Samia J. Khoury
- Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
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36
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Curran JM, Pu F, Chen R, Hunt JA. The use of dynamic surface chemistries to control msc isolation and function. Biomaterials 2011; 32:4753-60. [PMID: 21489621 DOI: 10.1016/j.biomaterials.2011.03.045] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Accepted: 03/19/2011] [Indexed: 01/28/2023]
Abstract
Material modifications can be used to induce cell responses, in particular-CH(3) and -NH(2) have shown potential in enhancing the ability of a material to support mesenchymal stem cell (MSC) adhesion and differentiation. Currently this process is variable, due to the lack of definition of controlled contextual presentation of the chemical group of interest across the surface. This paper defines the potential of -CH(3) modified surfaces, with optimised dynamic surface chemistry, to manipulate initial MSC adhesive events, integrin binding, and subsequent cell function. An array of -CH(3) silane modified glass substrates was produced using different -CH(3) chain lengths and mechanisms of bonding to the base substrate. We show that changing the chain length affects the ability of the surfaces to support viable adult MSC adhesion, directly related to induced FGF release, and expression of STRO-1, CD29, 73, 90 and 105. Chlorodimethyloctylsilane (ODMCS) modified surfaces resulted in significant increases of associated adult MSC markers compared to all other -CH(3) modified and control substrates. In contrast Dichlorodimethylsilane (DMDCS) modified surfaces did not support adult MSC adhesion due to high levels of early FGF release, which had an inhibitory effect on adult MSC culture, but enhanced the efficiency and cell selective properties of the substrate in isolation of multi-potent progenitor/MSC from adult human whole blood. Incorporation of optimised -CH(3) groups is a cost effective route for producing substrates that significantly enhance MSC isolation and expansion, highlighting the potential of the optimised substrates to replace RGD and fibronectin modifications in selected applications.
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Affiliation(s)
- J M Curran
- UKCTE, Clinical Engineering, The Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, United Kingdom.
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37
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Choi YH, Kurtz A, Stamm C. Mesenchymal stem cells for cardiac cell therapy. Hum Gene Ther 2011; 22:3-17. [PMID: 21062128 DOI: 10.1089/hum.2010.211] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy.
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Homing of endogenous stem/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives. Biomaterials 2011; 32:3189-209. [DOI: 10.1016/j.biomaterials.2010.12.032] [Citation(s) in RCA: 266] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Accepted: 12/21/2010] [Indexed: 12/11/2022]
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Sokolov MV, Neumann RD. Radiation-induced bystander effects in cultured human stem cells. PLoS One 2010; 5:e14195. [PMID: 21152027 PMCID: PMC2996280 DOI: 10.1371/journal.pone.0014195] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Accepted: 11/09/2010] [Indexed: 01/06/2023] Open
Abstract
Background The radiation-induced “bystander effect” (RIBE) was shown to occur in a number of experimental systems both in vitro and in vivo as a result of exposure to ionizing radiation (IR). RIBE manifests itself by intercellular communication from irradiated cells to non-irradiated cells which may cause DNA damage and eventual death in these bystander cells. It is known that human stem cells (hSC) are ultimately involved in numerous crucial biological processes such as embryologic development; maintenance of normal homeostasis; aging; and aging-related pathologies such as cancerogenesis and other diseases. However, very little is known about radiation-induced bystander effect in hSC. To mechanistically interrogate RIBE responses and to gain novel insights into RIBE specifically in hSC compartment, both medium transfer and cell co-culture bystander protocols were employed. Methodology/Principal Findings Human bone-marrow mesenchymal stem cells (hMSC) and embryonic stem cells (hESC) were irradiated with doses 0.2 Gy, 2 Gy and 10 Gy of X-rays, allowed to recover either for 1 hr or 24 hr. Then conditioned medium was collected and transferred to non-irradiated hSC for time course studies. In addition, irradiated hMSC were labeled with a vital CMRA dye and co-cultured with non-irradiated bystander hMSC. The medium transfer data showed no evidence for RIBE either in hMSC and hESC by the criteria of induction of DNA damage and for apoptotic cell death compared to non-irradiated cells (p>0.05). A lack of robust RIBE was also demonstrated in hMSC co-cultured with irradiated cells (p>0.05). Conclusions/Significance These data indicate that hSC might not be susceptible to damaging effects of RIBE signaling compared to differentiated adult human somatic cells as shown previously. This finding could have profound implications in a field of radiation biology/oncology, in evaluating radiation risk of IR exposures, and for the safety and efficacy of hSC regenerative-based therapies.
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Affiliation(s)
- Mykyta V Sokolov
- Nuclear Medicine Division, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America.
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