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Kaltchenko MV, Chien AL. Photoaging: Current Concepts on Molecular Mechanisms, Prevention, and Treatment. Am J Clin Dermatol 2025; 26:321-344. [PMID: 40072791 DOI: 10.1007/s40257-025-00933-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/14/2025]
Abstract
Photoaging is the consequence of chronic exposure to solar irradiation, encompassing ultraviolet (UV), visible, and infrared wavelengths. Over time, this exposure causes cumulative damage, leading to both aesthetic changes and structural degradation of the skin. These effects manifest as rhytids, dyschromia, textural changes, elastosis, volume loss, telangiectasias, and hyperkeratosis, collectively contributing to a prematurely aged appearance that exceeds the skin's chronological age. The hallmarks of photoaging vary significantly by skin phototype. Skin of color tends to exhibit dyschromia and features associated with "intrinsic" aging, such as volume loss, while white skin is more prone to "extrinsic" aging characteristics, including rhytids and elastosis. Moreover, susceptibility to different wavelengths within the electromagnetic spectrum also differs by skin phototype, influencing the clinical presentation of photoaging, as well as prevention and treatment strategies. Fortunately, photoaging-and its associated adverse effects-is largely preventable and, to some extent, reversible. However, effective prevention and treatment strategies require careful tailoring to an individual's skin type. In this review, we summarize molecular mechanisms underlying photoaging, examine its clinical manifestations, outline risk factors and prevention strategies, and highlight recent advancements in its treatment.
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Affiliation(s)
- Maria V Kaltchenko
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anna L Chien
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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2
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Ghasemzadeh-Hasankolaei M, Correia TR, Mano JF. Bioinstructive Liquefied Pockets in Hierarchical Hydrogels and Bioinks. Adv Healthc Mater 2025; 14:e2400286. [PMID: 39235370 DOI: 10.1002/adhm.202400286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/09/2024] [Indexed: 09/06/2024]
Abstract
This study proposes a novel, versatile, and modular platform for constructing porous and heterogeneous microenvironments based on the embedding of liquefied-based compartments in hydrogel systems. Using a bottom-up approach, microgels carrying the necessary cargo components, including cells and microparticles, are combined with a hydrogel precursor to fabricate a hierarchical structured (HS) system. The HS system possesses three key features that can be fully independently controlled: I) liquefied pockets enabling free cellular mobility; II) surface modified microparticles facilitating 3D microtissue organization inside the liquefied pockets; III) at a larger scale, the pockets are jammed in the hydrogel, forming a macro-sized construct. After crosslinking, the embedded microgels undergo a liquefaction process, forming a porous structure that ensures high diffusion of small biomolecules and enables cells to move freely within their miniaturized compartmentalized volume. More importantly, this platform allows the creation of multimodular cellular microenvironments within a hydrogel with controlled macrostructures, while decoupling micro- and macroenvironments. As a proof of concept, the enhancement of cellular functions using the HS system by encapsulating human adipose-derived mesenchymal stem cells (hASCs) is successfully demonstrated. Finally, the potential application of this system as a hybrid bioink for bioprinting complex 3D structures is showcased.
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Affiliation(s)
| | - Tiago R Correia
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, 3810-193, Portugal
| | - João F Mano
- CICECO-Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, 3810-193, Portugal
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3
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Lu Y, Su S, Chu CC, Kobayashi Y, Masoud AR, Peng H, Lien N, He M, Vuong C, Tran R, Hong S. Amino Acid-Based Protein-Mimic Hydrogel Incorporating Pro-Regenerative Lipid Mediator and Microvascular Fragments Promotes the Healing of Deep Burn Wounds. Int J Mol Sci 2024; 25:10378. [PMID: 39408708 PMCID: PMC11476471 DOI: 10.3390/ijms251910378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Pro-regenerative lipid mediator 1 (PreM1) is a specialized pro-resolving lipid mediator that promotes wound healing and regenerative functions of mesenchymal stem cells (MSCs), endothelial cells, and macrophages. The healing of third-degree (3°) burns and regenerative functions of MSCs are enhanced by ACgel1, an arginine-and-chitosan-based protein-mimic hybrid hydrogel. Adipose-tissue derived microvascular fragments (MVFs) are native vascularization units and a rich source of MSCs, endothelial cells, and perivascular cells for tissue regeneration. Here we describe an innovative PreM1-MVFs-ACgel1 construct that incorporated PreM1 and MVFs into ACgel1 via optimal design and fabrication. This construct delivered PreM1 to 3°-burn wounds at least up to 7 days-post-burn (dpb), and scaffolded and delivered MVFs. PreM1-MVFs-ACgel1 promoted the healing of 3°-burns in mice, including vascularization and collagen formation. The re-epithelization and closure of 3° burn wounds were promoted by ACgel1, MVFs, PreM1, MVFs-ACgel1, PreM1-ACgel1, or PreM1-MVFs-ACgel1 at certain time-point(s), while PreM1-MVFs-ACgel1 was most effective with 97% closure and 4.69% relative epithelial gap at 13 dpb compared to saline control. The PreM1-ACgel1 and MVFs-ACgel1 also promoted blood vessel regeneration of 3°-burns although PreM1-MVFs-ACgel1 is significantly more effective. These PreM1- and/or MVF-functionalized ACgel1 have nonexistent or minimal graft-donor requirements and are promising adjuvant therapeutic candidates for treating deep burns.
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Affiliation(s)
- Yan Lu
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Shanchun Su
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Chih-Chang Chu
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, NY 14853, USA
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Yuichi Kobayashi
- Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
- Organization for the Strategic Coordination of Research and Intellectual Properties, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
| | - Abdul-Razak Masoud
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Hongying Peng
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45221, USA
| | - Nathan Lien
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Mingyu He
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, NY 14853, USA
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Christopher Vuong
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Ryan Tran
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
| | - Song Hong
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, 2020 Gravier St., New Orleans, LA 70112, USA; (Y.L.); (A.-R.M.); (N.L.); (C.V.); (R.T.)
- Department of Ophthalmology, Louisiana State University Health, New Orleans, LA 70112, USA
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Lau CS, Park SY, Ethiraj LP, Singh P, Raj G, Quek J, Prasadh S, Choo Y, Goh BT. Role of Adipose-Derived Mesenchymal Stem Cells in Bone Regeneration. Int J Mol Sci 2024; 25:6805. [PMID: 38928517 PMCID: PMC11204188 DOI: 10.3390/ijms25126805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/13/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Bone regeneration involves multiple factors such as tissue interactions, an inflammatory response, and vessel formation. In the event of diseases, old age, lifestyle, or trauma, bone regeneration can be impaired which could result in a prolonged healing duration or requiring an external intervention for repair. Currently, bone grafts hold the golden standard for bone regeneration. However, several limitations hinder its clinical applications, e.g., donor site morbidity, an insufficient tissue volume, and uncertain post-operative outcomes. Bone tissue engineering, involving stem cells seeded onto scaffolds, has thus been a promising treatment alternative for bone regeneration. Adipose-derived mesenchymal stem cells (AD-MSCs) are known to hold therapeutic value for the treatment of various clinical conditions and have displayed feasibility and significant effectiveness due to their ease of isolation, non-invasive, abundance in quantity, and osteogenic capacity. Notably, in vitro studies showed AD-MSCs holding a high proliferation capacity, multi-differentiation potential through the release of a variety of factors, and extracellular vesicles, allowing them to repair damaged tissues. In vivo and clinical studies showed AD-MSCs favoring better vascularization and the integration of the scaffolds, while the presence of scaffolds has enhanced the osteogenesis potential of AD-MSCs, thus yielding optimal bone formation outcomes. Effective bone regeneration requires the interplay of both AD-MSCs and scaffolds (material, pore size) to improve the osteogenic and vasculogenic capacity. This review presents the advances and applications of AD-MSCs for bone regeneration and bone tissue engineering, focusing on the in vitro, in vivo, and clinical studies involving AD-MSCs for bone tissue engineering.
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Affiliation(s)
- Chau Sang Lau
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - So Yeon Park
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Lalith Prabha Ethiraj
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Priti Singh
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Grace Raj
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
| | - Jolene Quek
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (Y.C.)
| | - Somasundaram Prasadh
- Center for Clean Energy Engineering, University of Connecticut, Storrs, CT 06269, USA;
| | - Yen Choo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; (J.Q.); (Y.C.)
| | - Bee Tin Goh
- National Dental Centre Singapore, National Dental Research Institute Singapore, Singapore 168938, Singapore; (C.S.L.); (S.Y.P.); (L.P.E.); (G.R.)
- Oral Health Academic Clinical Programme, Duke-NUS Medical School, Singapore 169857, Singapore
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Velikova T, Dekova T, Miteva DG. Controversies regarding transplantation of mesenchymal stem cells. World J Transplant 2024; 14:90554. [PMID: 38947963 PMCID: PMC11212595 DOI: 10.5500/wjt.v14.i2.90554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/07/2024] [Accepted: 04/03/2024] [Indexed: 06/13/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have tantalized regenerative medicine with their therapeutic potential, yet a cloud of controversies looms over their clinical transplantation. This comprehensive review navigates the intricate landscape of MSC controversies, drawing upon 15 years of clinical experience and research. We delve into the fundamental properties of MSCs, exploring their unique immunomodulatory capabilities and surface markers. The heart of our inquiry lies in the controversial applications of MSC transplantation, including the perennial debate between autologous and allogeneic sources, concerns about efficacy, and lingering safety apprehensions. Moreover, we unravel the enigmatic mechanisms surrounding MSC transplantation, such as homing, integration, and the delicate balance between differentiation and paracrine effects. We also assess the current status of clinical trials and the ever-evolving regulatory landscape. As we peer into the future, we examine emerging trends, envisioning personalized medicine and innovative delivery methods. Our review provides a balanced and informed perspective on the controversies, offering readers a clear understanding of the complexities, challenges, and potential solutions in MSC transplantation.
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Affiliation(s)
- Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Tereza Dekova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
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Ghasemzadeh-Hasankolaei M, Pinto CA, Jesus D, Saraiva JA, Mano JF. Effect of high cyclic hydrostatic pressure on osteogenesis of mesenchymal stem cells cultured in liquefied micro-compartments. Mater Today Bio 2023; 23:100861. [PMID: 38058695 PMCID: PMC10696388 DOI: 10.1016/j.mtbio.2023.100861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 11/04/2023] [Accepted: 11/09/2023] [Indexed: 12/08/2023] Open
Abstract
Bone resident cells are constantly subjected to a range of distinct mechanical loadings, which generates a complex microenvironment. In particular, hydrostatic pressure (HP) has a key impact on modulation of cell function and fate determination. Although HP is a constant mechanical stimulus, its role in regulating the osteogenesis process within a defined 3D microenvironment has not been comprehensively elucidated. Perceiving how environmental factors regulate the differentiation of stem cells is essential for expanding their regenerative potential. Inspired by the mechanical environment of bone, this study attempted to investigate the influence of different ranges of cyclic HP on human adipose-derived mesenchymal stem cells (MSCs) encapsulated within a compartmentalized liquefied microenvironment. Taking advantage of the liquefied environment of microcapsules, MSCs were exposed to cyclic HP of 5 or 50 MPa, 3 times/week at 37 °C. Biological tests using fluorescence staining of F-actin filaments showed a noticeable improvement in cell-cell interactions and cellular network formation of MSCs. These observations were more pronounced in osteogenic (OST) condition, as confirmed by fluorescent staining of vinculin. More interestingly, there was a significant increase in alkaline phosphatase activity of MSCs exposed to 50 MPa magnitude of HP, even in the absence of osteoinductive factors. In addition, a greater staining area of both osteopontin and hydroxyapatite was detected in the 50 MPa/OST group. These findings highlight the benefit of hydrostatic pressure to regulate osteogenesis of MSCs as well as the importance of employing simultaneous biochemical and mechanical stimulation to accelerate the osteogenic potential of MSCs for biomedical purposes.
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Affiliation(s)
| | - Carlos A. Pinto
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Diana Jesus
- CICECO–Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Jorge A. Saraiva
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - João F. Mano
- CICECO–Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
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Baron M, Drohat P, Crawford B, Hornicek FJ, Best TM, Kouroupis D. Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients. Bioengineering (Basel) 2023; 10:1187. [PMID: 37892917 PMCID: PMC10604230 DOI: 10.3390/bioengineering10101187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Osteosarcoma (OS) is a type of bone cancer that is derived from primitive mesenchymal cells typically affecting children and young adults. The current standard of treatment is a combination of neoadjuvant chemotherapy and surgical resection of the cancerous bone. Post-resection challenges in bone regeneration arise. To determine the appropriate amount of bone to be removed, preoperative imaging techniques such as bone and CT scans are employed. To prevent local recurrence, the current standard of care suggests maintaining bony and soft tissue margins from 3 to 7 cm beyond the tumor. The amount of bone removed in an OS patient leaves too large of a deficit for bone to form on its own and requires reconstruction with metal implants or allografts. Both methods require the bone to heal, either to the implant or across the allograft junction, often in the setting of marrow-killing chemotherapy. Therefore, the issue of bone regeneration within the surgically resected margins remains an important challenge for the patient, family, and treating providers. Mesenchymal stem/stromal cells (MSCs) are potential agents for enhancing bone regeneration post tumor resection. MSCs, used with scaffolds and growth factors, show promise in fostering bone regeneration in OS cases. We spotlight two MSC types-bone marrow-derived (BM-MSCs) and adipose tissue-derived (ASCs)-highlighting their bone regrowth facilitation and immunomodulatory effects on immune cells like macrophages and T cells, enhancing therapeutic outcomes. The objective of this review is two-fold: review work demonstrating any ability of MSCs to target the deranged immune system in the OS microenvironment, and synthesize the available literature on the use of MSCs as a therapeutic option for stimulating bone regrowth in OS patients post bone resection. When it comes to repairing bone defects, both MB-MSCs and ASCs hold great potential for stimulating bone regeneration. Research has showcased their effectiveness in reconstructing bone defects while maintaining a non-tumorigenic role following wide resection of bone tumors, underscoring their capability to enhance bone healing and regeneration following tumor excisions.
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Affiliation(s)
- Max Baron
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Philip Drohat
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Brooke Crawford
- Sarcoma Biology Laboratory, Department of Orthopedics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (B.C.); (F.J.H.)
| | - Francis J. Hornicek
- Sarcoma Biology Laboratory, Department of Orthopedics, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (B.C.); (F.J.H.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (M.B.); (P.D.); (T.M.B.)
- Diabetes Research Institute, Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Romano IR, D’Angeli F, Vicario N, Russo C, Genovese C, Lo Furno D, Mannino G, Tamburino S, Parenti R, Giuffrida R. Adipose-Derived Mesenchymal Stromal Cells: A Tool for Bone and Cartilage Repair. Biomedicines 2023; 11:1781. [PMID: 37509421 PMCID: PMC10376676 DOI: 10.3390/biomedicines11071781] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
The osteogenic and chondrogenic differentiation ability of adipose-derived mesenchymal stromal cells (ASCs) and their potential therapeutic applications in bone and cartilage defects are reported in this review. This becomes particularly important when these disorders can only be poorly treated by conventional therapeutic approaches, and tissue engineering may represent a valuable alternative. Being of mesodermal origin, ASCs can be easily induced to differentiate into chondrocyte-like and osteocyte-like elements and used to repair damaged tissues. Moreover, they can be easily harvested and used for autologous implantation. A plethora of ASC-based strategies are being developed worldwide: they include the transplantation of freshly harvested cells, in vitro expanded cells or predifferentiated cells. Moreover, improving their positive effects, ASCs can be implanted in combination with several types of scaffolds that ensure the correct cell positioning; support cell viability, proliferation and migration; and may contribute to their osteogenic or chondrogenic differentiation. Examples of these strategies are described here, showing the enormous therapeutic potential of ASCs in this field. For safety and regulatory issues, most investigations are still at the experimental stage and carried out in vitro and in animal models. Clinical applications have, however, been reported with promising results and no serious adverse effects.
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Affiliation(s)
- Ivana Roberta Romano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
| | - Floriana D’Angeli
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Nunzio Vicario
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
| | - Carlo Genovese
- Faculty of Medicine and Surgery, “Kore” University of Enna, 94100 Enna, Italy;
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
| | - Giuliana Mannino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Serena Tamburino
- Chi.Pla Chirurgia Plastica, Via Suor Maria Mazzarello, 54, 95128 Catania, Italy;
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (I.R.R.); (N.V.); (C.R.); (R.P.); (R.G.)
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Microbiological Aspects of Pharmaceutical Manufacturing of Adipose-Derived Stem Cell-Based Medicinal Products. Cells 2023; 12:cells12050680. [PMID: 36899816 PMCID: PMC10000438 DOI: 10.3390/cells12050680] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/08/2023] [Accepted: 02/14/2023] [Indexed: 02/24/2023] Open
Abstract
Subcutaneous adipose tissue is an excellent source of mesenchymal stem cells (ADSCs), which can be used in cell therapies as an active substance in advanced therapy medicinal products (ATMPs). Because of the short shelf-life of ATMPs and the time needed to obtain the results of microbiological analysis, the final product is often administered to the patient before sterility is confirmed. Because the tissue used for cell isolation is not sterilized to maintain cell viability, controlling and ensuring microbiological purity at all stages of production is crucial. This study presents the results of monitoring the contamination incidence during ADSC-based ATMP manufacturing over two years. It was found that more than 40% of lipoaspirates were contaminated with thirteen different microorganisms, which were identified as being physiological flora from human skin. Such contamination was successfully eliminated from the final ATMPs through the implementation of additional microbiological monitoring and decontamination steps at various stages of production. Environmental monitoring revealed incidental bacterial or fungal growth, which did not result in any product contamination and was reduced thanks to an effective quality assurance system. To conclude, the tissue used for ADSC-based ATMP manufacturing should be considered contaminated; therefore, good manufacturing practices specific to this type of product must be elaborated and implemented by the manufacturer and the clinic in order to obtain a sterile product.
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Moreno-Garcia A, Rodriguez-Merchan EC. Orthobiologics: Current role in Orthopedic Surgery and Traumatology. THE ARCHIVES OF BONE AND JOINT SURGERY 2022; 10:536-542. [PMID: 36032640 PMCID: PMC9382248 DOI: 10.22038/abjs.2021.52770.2614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/30/2021] [Indexed: 01/24/2023]
Abstract
Orthobiologics are organic and synthetic materials that help in the cure of musculo-skeletal problems and are utilized in Orthopaedic Surgery, both in and out of the surgical theater, to augment the possibilities of curing bone and soft tissue lesions. Taking into account that their effect is frequently multifactorial and, in some occasions not entirely comprehended, together with the insufficient clinical information, orthobiologics should be scrupulously assessed against other secure and clinically accepted options. The fundamental orthobiologics today ready for use in Orthopedic Surgery are the following: osseous hollow fillers, extracellular matrix (ECM) substances, platelet-rich plasma (PRP), bone morphogenetic protein-2 (BMP-2), bone marrow aspirate (BMA), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cells (MSCs). It is predictable that in the time to come we will have more secure and more efficacious orthobiologics. Meanwhile, it is paramount that orthopedic surgeons have appropriate information of contemporary orthobiologics (biological adjuvants) so that they can utilize them correctly.
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Rahman G, Frazier TP, Gimble JM, Mohiuddin OA. The Emerging Use of ASC/Scaffold Composites for the Regeneration of Osteochondral Defects. Front Bioeng Biotechnol 2022; 10:893992. [PMID: 35845419 PMCID: PMC9280640 DOI: 10.3389/fbioe.2022.893992] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Articular cartilage is composed of chondrocytes surrounded by a porous permeable extracellular matrix. It has a limited spontaneous healing capability post-injury which, if left untreated, can result in severe osteochondral disease. Currently, osteochondral (OC) defects are treated by bone marrow stimulation, artificial joint replacement, or transplantation of bone, cartilage, and periosteum, while autologous osteochondral transplantation is also an option; it carries the risk of donor site damage and is limited only to the treatment of small defects. Allografts may be used for larger defects; however, they have the potential to elicit an immune response. A possible alternative solution to treat osteochondral diseases involves the use of stromal/stem cells. Human adipose-derived stromal/stem cells (ASCs) can differentiate into cartilage and bone cells. The ASC can be combined with both natural and synthetic scaffolds to support cell delivery, growth, proliferation, migration, and differentiation. Combinations of both types of scaffolds along with ASCs and/or growth factors have shown promising results for the treatment of OC defects based on in vitro and in vivo experiments. Indeed, these findings have translated to several active clinical trials testing the use of ASC-scaffold composites on human subjects. The current review critically examines the literature describing ASC-scaffold composites as a potential alternative to conventional therapies for OC tissue regeneration.
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Affiliation(s)
- Gohar Rahman
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | | | | | - Omair A. Mohiuddin
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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12
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Labusca L. Adipose tissue in bone regeneration - stem cell source and beyond. World J Stem Cells 2022; 14:372-392. [PMID: 35949397 PMCID: PMC9244952 DOI: 10.4252/wjsc.v14.i6.372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/30/2021] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
Adipose tissue (AT) is recognized as a complex organ involved in major home-ostatic body functions, such as food intake, energy balance, immunomodulation, development and growth, and functioning of the reproductive organs. The role of AT in tissue and organ homeostasis, repair and regeneration is increasingly recognized. Different AT compartments (white AT, brown AT and bone marrow AT) and their interrelation with bone metabolism will be presented. AT-derived stem cell populations - adipose-derived mesenchymal stem cells and pluripotent-like stem cells. Multilineage differentiating stress-enduring and dedifferentiated fat cells can be obtained in relatively high quantities compared to other sources. Their role in different strategies of bone and fracture healing tissue engineering and cell therapy will be described. The current use of AT- or AT-derived stem cell populations for fracture healing and bone regenerative strategies will be presented, as well as major challenges in furthering bone regenerative strategies to clinical settings.
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Affiliation(s)
- Luminita Labusca
- Magnetic Materials and Sensors, National Institute of Research and Development for Technical Physics, Iasi 700050, Romania
- Orthopedics and Traumatology, County Emergency Hospital Saint Spiridon Iasi, Iasi 700050, Romania.
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13
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Yoo KH, Thapa N, Chwae YJ, Yoon SH, Kim BJ, Lee JO, Jang YN, Kim J. Transforming growth factor‑β family and stem cell‑derived exosome therapeutic treatment in osteoarthritis (Review). Int J Mol Med 2022; 49:62. [PMID: 35293597 PMCID: PMC8930092 DOI: 10.3892/ijmm.2022.5118] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/01/2022] [Indexed: 11/21/2022] Open
Abstract
Osteoarthritis (OA), although extensively researched, still lacks an effective and safe treatment. The only current treatment option available for advanced OA is joint replacement surgery. This surgery may pose the risks of persistent pain, surgical complications and limited implant lifespan. Transforming growth factor (TGF)‑β has a crucial role in multiple cellular processes such as cell proliferation. Any deterioration in TGF‑β signaling pathways can have an immense impact on OA. Owing to the crucial role of TGF‑β in cartilage homeostasis, targeting it could be an alternative therapeutic approach. Additionally, stem cell‑based therapy has recently emerged as an effective treatment strategy that could replace surgery. A number of recent findings suggest that the tissue regeneration effect of stem cells is attributed to the paracrine secretion of anti‑inflammatory and chondroprotective mediators or trophic factors, particularly nanosized extracellular vesicles (i.e., exosomes). Literature searches were performed in the MEDLINE, EMBASE, Cochrane Library and PubMed electronic database for relevant articles published before September 2021. Multiple investigators have confirmed TGF‑β3 as a promising candidate which has the chondrogenic potential to repair articular cartilage degeneration. Combining TGF‑β3 with bone morphogenetic proteins‑6, which has synergistic effect on chondrogenesis, with an efficient platform such as exosomes, which themselves possess a chondroprotective function, offers an innovative and more efficient approach to treat injured cartilage. In addition, multiple findings stating the role of exosomes in chondroprotection has also verified a similar fact showing exosomes may be a more favorable choice than the source itself. In the present review, the importance of TGF‑β family in OA and the possibility of therapeutic treatment using stem cell‑derived exosomes are described.
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Affiliation(s)
- Kwang Ho Yoo
- Department of Dermatology, Chung‑Ang University College of Medicine, Seoul 06973, Republic of Korea
| | - Nikita Thapa
- CK‑Exogene, Inc., Seongnam, Gyeonggi‑do 13201, Republic of Korea
| | - Yong Joon Chwae
- Department of Microbiology, Ajou University School of Medicine, Suwon, Gyeonggi‑do 16499, Republic of Korea
| | - Seung Hyun Yoon
- Department of Physical Medicine and Rehabilitation, Ajou University School of Medicine, Suwon, Gyeonggi‑do 16499, Republic of Korea
| | - Beom Joon Kim
- Department of Dermatology, Chung‑Ang University College of Medicine, Seoul 06973, Republic of Korea
| | - Jung Ok Lee
- Department of Dermatology, Chung‑Ang University College of Medicine, Seoul 06973, Republic of Korea
| | - You Na Jang
- Department of Dermatology, Chung‑Ang University College of Medicine, Seoul 06973, Republic of Korea
| | - Jaeyoung Kim
- CK‑Exogene, Inc., Seongnam, Gyeonggi‑do 13201, Republic of Korea
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14
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Smakaj A, De Mauro D, Rovere G, Pietramala S, Maccauro G, Parolini O, Lattanzi W, Liuzza F. Clinical Application of Adipose Derived Stem Cells for the Treatment of Aseptic Non-Unions: Current Stage and Future Perspectives-Systematic Review. Int J Mol Sci 2022; 23:3057. [PMID: 35328476 PMCID: PMC8950719 DOI: 10.3390/ijms23063057] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 12/18/2022] Open
Abstract
Fracture non-union is a challenging orthopaedic issue and a socio-economic global burden. Several biological therapies have been introduced to improve traditional surgical approaches. Among these, the latest research has been focusing on adipose tissue as a powerful source of mesenchymal stromal cells, namely, adipose-derived stem cells (ADSCs). ADSC are commonly isolated from the stromal vascular fraction (SVF) of liposuctioned hypodermal adipose tissue, and their applications have been widely investigated in many fields, including non-union fractures among musculoskeletal disorders. This review aims at providing a comprehensive update of the literature on clinical application of ADSCs for the treatment of non-unions in humans. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Only three articles met our inclusion criteria, with a total of 12 cases analyzed for demographics and harvesting, potential manufacturing and implantation of ADSCs. The review of the literature suggests that adipose derived cell therapy can represent a promising alternative in bone regenerative medicine for the enhancement of non-unions and bone defects. The low number of manuscripts reporting ADSC-based therapies for long bone fracture healing suggests some critical issues that are discussed in this review. Nevertheless, further investigations on human ADSC therapies are needed to improve the knowledge on their translational potential and to possibly achieve a consensus on their use for such applications.
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Affiliation(s)
- Amarildo Smakaj
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Domenico De Mauro
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giuseppe Rovere
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Silvia Pietramala
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giulio Maccauro
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
- Department of Geriatrics and Orthopaedic Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy
| | - Wanda Lattanzi
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Liuzza
- Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (A.S.); (D.D.M.); (G.R.); (S.P.); (G.M.)
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15
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Characterization and functional analysis of the adipose tissue-derived stromal vascular fraction of pediatric patients with osteogenesis imperfecta. Sci Rep 2022; 12:2414. [PMID: 35165317 PMCID: PMC8844034 DOI: 10.1038/s41598-022-06063-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/12/2022] [Indexed: 11/08/2022] Open
Abstract
AbstractPediatric patients with Osteogenesis Imperfecta (OI), a heritable connective tissue disorder, frequently suffer from long bone deformations. Surgical correction often results in bone non-unions, necessitating revision surgery with autogenous bone grafting using bone-marrow-derived stem cells (BM-SC) to regenerate bone. BM-SC harvest is generally invasive and limited in supply; thus, adipose tissue's stromal vascular fraction (SVF) has been introduced as an alternative stem cell reservoir. To elucidate if OI patients' surgical site dissected adipose tissue could be used as autologous bone graft in future, we investigated whether the underlying genetic condition alters SVF's cell populations and in vitro differentiation capacity. After optimizing SVF isolation, we demonstrate successful isolation of SVF of pediatric OI patients and non-OI controls. The number of viable cells was comparable between OI and controls, with about 450,000 per gram tissue. Age, sex, type of OI, disease-causing collagen mutation, or anatomical site of harvest did not affect cell outcome. Further, SVF-containing cell populations were similar between OI and controls, and all isolated SVF's demonstrated chondrogenic, adipogenic, and osteogenic differentiation capacity in vitro. These results indicate that SVF from pediatric OI patients could be used as a source of stem cells for autologous stem cell therapy in OI.
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16
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Wu CC, Chen YC, Wu YC, Huang SH, Kuo YR, Lee SS. Foraging for the Optimal Dressing Scaffold to Carry Adipose-Derived Stromal/Progenitor Cells for Cell Therapy. Cell Transplant 2022; 31:9636897221113798. [PMID: 35876233 PMCID: PMC9326840 DOI: 10.1177/09636897221113798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In our daily plastic surgery practice, we have seen many chronic wounds that need new biotechnology to help and improve wound healing. Stem cells play a crucial role in regenerative medicine. Many pre-clinical researches had reported the beneficial paracrine effects of stem cell therapy for chronic wounds. Cell-friendly scaffolds may provide the protection and three-dimensional space required for adherence of stem cells, thus allowing these stem cells to proliferate and differentiate for treatment purpose. A successful scaffold may enhance the effects of stem cell therapy. In this presented series, the authors attempted to identify the most suitable scaffolds from several commercially available wound dressings that could sustain adipose-derived stromal/progenitor cells (ADSCs) survival. Therefore, we isolated ADSCs containing the green fluorescent protein (GFP) from GFP transgenic rats. The GFP (+) ADSCs and their progenies could be easily observed using a fluorescence microscope. Moreover, we analyzed the cytokines secreted in condition medium (CM) to understand the activities of ADSCs in various dressings. Our results showed that the foam dressings, hydrofiber, chitosan, and alginate plus carboxymethylcellulose were identified as the most suitable dressing materials. Higher concentrations of transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) were observed 48 h after loading them with GFP (+) ADSCs. Therefore, multiple topical cell therapy using ADSCs can be performed by applying suitable dressing scaffolds without repeated needle injections to deliver the stem cells into the wound bed. Based on their fluorescence property, the GFP (+) ADSCs can also possibly be used for testing biocompatibility of medical materials in the future.
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Affiliation(s)
- Chia-Chieh Wu
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua, Taiwan.,Orthopedic Surgery Department, Changhua Christian Hospital, Changhua, Taiwan.,Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ying-Che Chen
- Department of Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
| | - Yi-Chia Wu
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Hung Huang
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yur-Ren Kuo
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Su-Shin Lee
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Surgery, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.,Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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17
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Li Y, Fu G, Gong Y, Li B, Li W, Liu D, Yang X. BMP-2 promotes osteogenic differentiation of mesenchymal stem cells by enhancing mitochondrial activity. JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS 2022; 22:123-131. [PMID: 35234167 PMCID: PMC8919656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) have become seed cells and basic elements for bone regeneration and bone tissue engineering. The aim of the present study was to investigate the roles and mechanisms of bone morphogenetic protein 2 (BMP-2) on osteogenic differentiation of MSCs. METHODS Primary MSCs were isolated from the femur and tibia bone of rats and then transfected with BMP-2 and PGC-1α adenovirus vectors. Alkaline phosphatase (ALP) activity and alizarin red staining were used to measure osteogenic differentiation of MSCs. Real-time PCR and western blot assays were performed to assess osteogenic differentiation-related proteins levels. The activities of mitochondrial respiratory chain complexes I and II and mitochondrial fluorescence intensity were used to explore mitochondria status during osteogenic differentiation of MSCs. RESULTS We found that the ability of BMP-2 overexpressed (OE) group osteogenic differentiation was significantly improved, compared with the negative control (NC) group. The results also indicated that BMP-2 can promote the activity of mitochondria. We further used the gain- and loss-of-function approaches to demonstrate that BMP-2 promotes mitochondrial activity by up-regulating PGC-1α to promote osteogenic differentiation of MSCs. CONCLUSIONS These results explored the important role of BMP-2 in the osteoblast differentiation of MSCs from a new perspective, providing a theoretical and experimental basis for bone defect and repair.
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Affiliation(s)
- Yinan Li
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Guangmin Fu
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Yahui Gong
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Bo Li
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Wei Li
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Dacheng Liu
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China
| | - Xiaoning Yang
- Department of Orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, China,Corresponding author: Xiaoning Yang, Department of orthopaedics, Xuzhou No.1 People’s Hospital, Xuzhou, 221000, China E-mail:
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18
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Jiang W, Zhang J, Zhang X, Fan C, Huang J. VAP-PLGA microspheres (VAP-PLGA) promote adipose-derived stem cells (ADSCs)-induced wound healing in chronic skin ulcers in mice via PI3K/Akt/HIF-1α pathway. Bioengineered 2021; 12:10264-10284. [PMID: 34720043 PMCID: PMC8810082 DOI: 10.1080/21655979.2021.1990193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/01/2021] [Accepted: 10/02/2021] [Indexed: 12/23/2022] Open
Abstract
Chronic skin ulcers are a primary global health problem. Velvet antler polypeptide (VAP) regulates endothelial cell migration and angiogenic sprout. Adipose-derived stem cells (ADSCs) are reported to make pivotal impacts upon wound healing. This study aimed to explore the role of VAP combined with ADSCs in wound healing of chronic skin ulcers. The effect of VAP on phenotypes of ADSCs, and VAP (PLGA microspheres) combining with ADSCs on wound healing of chronic skin ulcers in vivo was evaluated. VAP generally promoted the proliferation, migration and invasion of ADSCs, and ADSC-induced angiogenesis in human umbilical vein endothelial cells (HUVECs) through PI3K/Akt/HIF-1α pathway. VAP-PLGA (PLGA microspheres) enhanced the promoting effect of ADSCs on wound healing, pathological changes, and angiogenesis in chronic skin ulcers in vivo. VAP-PLGA intensified the effect of ADSCs on up-regulating the levels of p-PI3K/PI3K, p-Akt/Akt, HIF-1α, vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), C-X-C motif chemokine receptor 4 (CXCR4), angiopoietin-4 (Ang-4), VEGF receptor (VEGFR), and transforming growth factor-β1 (TGF-β1), and down-regulating the levels of interleukin-1 β (IL-1β), IL-18 and IL-6 in wound tissues in chronic skin ulcers in vivo. Collectively, VAP promoted the growth, migration, invasion, and angiogenesis of ADSCs through activating PI3K/Akt/HIF-1α pathway, and VAP-PLGA enhanced the function of ADSCs in promoting wound healing in vivo, which was associated with angiogenesis, inflammation inhibition, and dermal collagen synthesis.
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Affiliation(s)
- Wen Jiang
- First Clinical School Medicine, Nanjing University of Chinese Medicine, Nanjing City, China
| | - Jun Zhang
- Department of Plastic Surgery, Affiliated Hospital Nanjing University of Chinese Medicine, Nanjing City, China
| | - Xudong Zhang
- Department of Aesthetic and Plastic Surgery, 903RD Hospital of Pla, Hangzhou City, China
| | - Chenghong Fan
- Aesthetic Surgery Department, Lishui Fan Chenghong Medical Aesthetic Clinic, Lishui City, China
| | - Jinlong Huang
- Department of Plastic Surgery, Affiliated Hospital Nanjing University of Chinese Medicine, Nanjing City, China
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19
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Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis. Biomedicines 2021; 9:1598. [PMID: 34829827 PMCID: PMC8615475 DOI: 10.3390/biomedicines9111598] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Minju Kim
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
| | - Myunghee Yoon
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (C.L.); (M.K.); (J.H.)
- Departments of Biological Sciences, Pusan National University, Pusan 46241, Korea
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20
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Qi J, Yu T, Hu B, Wu H, Ouyang H. Current Biomaterial-Based Bone Tissue Engineering and Translational Medicine. Int J Mol Sci 2021; 22:10233. [PMID: 34638571 PMCID: PMC8508818 DOI: 10.3390/ijms221910233] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/14/2021] [Accepted: 09/19/2021] [Indexed: 11/16/2022] Open
Abstract
Bone defects cause significant socio-economic costs worldwide, while the clinical "gold standard" of bone repair, the autologous bone graft, has limitations including limited graft supply, secondary injury, chronic pain and infection. Therefore, to reduce surgical complexity and speed up bone healing, innovative therapies are needed. Bone tissue engineering (BTE), a new cross-disciplinary science arisen in the 21st century, creates artificial environments specially constructed to facilitate bone regeneration and growth. By combining stem cells, scaffolds and growth factors, BTE fabricates biological substitutes to restore the functions of injured bone. Although BTE has made many valuable achievements, there remain some unsolved challenges. In this review, the latest research and application of stem cells, scaffolds, and growth factors in BTE are summarized with the aim of providing references for the clinical application of BTE.
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Affiliation(s)
- Jingqi Qi
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
- Zhejiang University-University of Edinburgh Institute, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Tianqi Yu
- Department of Mechanical Engineering, Zhejiang University-University of Illinois at Urbana-Champaign Institute, Zhejiang University, Haining 314400, China;
| | - Bangyan Hu
- Section of Molecular and Cell Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA;
| | - Hongwei Wu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
- Zhejiang University-University of Edinburgh Institute, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
- Zhejiang University-University of Edinburgh Institute, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou 310003, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310003, China
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21
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Schneider C, Dungel P, Priglinger E, Danzer M, Schädl B, Nürnberger S. The impact of photobiomodulation on the chondrogenic potential of adipose-derived stromal/stem cells. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2021; 221:112243. [PMID: 34217028 DOI: 10.1016/j.jphotobiol.2021.112243] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/23/2021] [Accepted: 06/16/2021] [Indexed: 01/11/2023]
Abstract
Due to their capacity to differentiate into the chondrogenic lineage, adipose-derived stromal/stem cells (ASC) are a promising source of therapeutically relevant cells for cartilage tissue regeneration. Their differentiation potential, however, varies between patients. In our study, we aim to stimulate ASC towards a more reliable chondrogenic phenotype using photobiomodulation (PBM). LED devices of either blue (475 nm), green (516 nm) or red (635 nm) light were used to treat human ASC from donors of varying chondrogenic potential. The treatment was applied either once during the 2D expansion phase or repeatedly during the 3D differentiation phase. Chondrogenic differentiation was assessed via pellet size, GAG/DNA content, histology and gene expression analysis. Reactions to PBM were found to be wavelength-dependent and more pronounced when the treatment was applied during expansion. Donors were assigned to responder categories according to their response to the treatment during expansion, whereby good responders were mainly donors with low intrinsic chondrogenic potential. Exposed to light, they revealed a particularly high relative increase in pellet size (more than twice the size of untreated controls after red light PBM), intense collagen type II immunostaining (low/absent in untreated controls) and activation of otherwise absent COL2A1 expression. Conversely, on a donor with high intrinsic chondrogenic potential, light had adverse effects. When applied with shorter wavelengths (blue, green), it led to reduced pellet size, GAG/DNA content and collagen type II immunostaining. However, when PBM was applied in 3D, the same donor was the only one to react with increased differentiation to all three wavelengths. We were able to demonstrate that PBM can be used to enhance or hamper chondrogenesis of ASC, and that success depends on treatment parameters and intrinsic cellular potential. The improvement of chondrogenesis in donors with low intrinsic potential highlights PBM as potent tool for cell-based cartilage regeneration. Its cost-effectiveness and ease of use make for an attractive treatment option to enhance the performance of ASC in cartilage tissue engineering.
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Affiliation(s)
- C Schneider
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Center, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - P Dungel
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Center, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - E Priglinger
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Center, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - M Danzer
- Austrian Red Cross Blood Transfusion Service of Upper Austria, Linz, Austria
| | - B Schädl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Center, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria; University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - S Nürnberger
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Trauma Research Center, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria; Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, Vienna, Austria
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Comparison of the Donor Age-Dependent and In Vitro Culture-Dependent Mesenchymal Stem Cell Aging in Rat Model. Stem Cells Int 2021; 2021:6665358. [PMID: 34093710 PMCID: PMC8140846 DOI: 10.1155/2021/6665358] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/12/2021] [Accepted: 04/27/2021] [Indexed: 12/14/2022] Open
Abstract
Clinical experiments suggest that mesenchymal stem cells (MSCs) may be useful for tissue repair therapies or treatment of the autoimmune disorders. There is still lack of consensus concerning the age limit of MSC donors, majority of researchers suggest the autologous MSC therapies of patients not exceeding age limit of 55-60 yrs. The purpose of our study was to compare the selected parameters of MSCs from adipose tissue (adipose stem cell, ASC) collected from young and old rats of ages corresponding to patient's ages 25 yrs. and 80 yrs., respectively. The differences of parameters of ASCs from young and old animals were compared with the differences between ASCs from short-term (3 passage) and long-term (30 passage) in vitro culture. Cell morphology, surface marker expression, growth potential, metabolic activity, β-galactosidase activity, clonogenic potential, angiogenic potential, and differentiation ability of ASCs from young and aged animals and from in vitro cultures at 3rd and 30th passages were compared and analyzed. It may be concluded that ASCs may be applied for autologous transplantations in aged patients. Comparison of ASC aging dynamics depending on host aging or in vitro culture duration suggests that long-term in vitro culture may affect ASCs more than natural aging process of their host. We suggest that ASCs expanded in vitro prior to their clinical use must be carefully screened for the possible aging effects resulting not only from donor age, but from the duration of their in vitro culture.
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Mende W, Götzl R, Kubo Y, Pufe T, Ruhl T, Beier JP. The Role of Adipose Stem Cells in Bone Regeneration and Bone Tissue Engineering. Cells 2021; 10:cells10050975. [PMID: 33919377 PMCID: PMC8143357 DOI: 10.3390/cells10050975] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Bone regeneration is a complex process that is influenced by tissue interactions, inflammatory responses, and progenitor cells. Diseases, lifestyle, or multiple trauma can disturb fracture healing, which might result in prolonged healing duration or even failure. The current gold standard therapy in these cases are bone grafts. However, they are associated with several disadvantages, e.g., donor site morbidity and availability of appropriate material. Bone tissue engineering has been proposed as a promising alternative. The success of bone-tissue engineering depends on the administered cells, osteogenic differentiation, and secretome. Different stem cell types offer advantages and drawbacks in this field, while adipose-derived stem or stromal cells (ASCs) are in particular promising. They show high osteogenic potential, osteoinductive ability, and immunomodulation properties. Furthermore, they can be harvested through a noninvasive process in high numbers. ASCs can be induced into osteogenic lineage through bioactive molecules, i.e., growth factors and cytokines. Moreover, their secretome, in particular extracellular vesicles, has been linked to fracture healing. The aim of this review is a comprehensive overview of ASCs for bone regeneration and bone tissue engineering.
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Affiliation(s)
- Wolfgang Mende
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Rebekka Götzl
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Yusuke Kubo
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Tim Ruhl
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
| | - Justus P Beier
- Hand Surgery-Burn Center, Department of Plastic Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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Khatkar H, See A. Stem Cell Therapy in the Management of Fracture Non-Union - Evaluating Cellular Mechanisms and Clinical Progress. Cureus 2021; 13:e13869. [PMID: 33859917 PMCID: PMC8038927 DOI: 10.7759/cureus.13869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Bone, as a physiological and anatomical construct, displays remarkable intrinsic healing capacity. The overwhelming majority of fractures will heal satisfactorily, if aligned anatomically, compressed and immobilised appropriately. Of the 10% of fractures that do not heal, even under ideal mechanical and biological conditions, further consideration must be given to augment bone healing. Management strategies for non-union pose a significant clinical challenge to the practicing orthopaedic surgeon. Stem cell therapy is beginning to demonstrate significant potential for augmented bone repair in the context of non-union. This review attempts to contextualise the function of stem cells within this clinical setting, reviewing the relevant cellular mechanisms and clinical applications. From evaluating the literature base, there is a lack of high-quality evidence examining the role of mesenchymal stem cells (MSCs) within this research focus. Appropriately designed randomised controlled trials are required to evaluate this research area further, with a view to guiding future treatment options for the practicing orthopaedic surgeon.
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Affiliation(s)
- Harman Khatkar
- Trauma and Orthopaedics, Royal Berkshire Hospital, Reading, GBR.,Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, GBR
| | - Abbas See
- Trauma and Orthopaedics, Kettering General Hospital, Kettering, GBR
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25
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Wu Q, He S, Zhu Y, Pu S, Zhou Z. Antiobesity Effects of Adipose-Derived Stromal/Stem Cells in a Naturally Aged Mouse Model. Obesity (Silver Spring) 2021; 29:133-142. [PMID: 33185001 DOI: 10.1002/oby.23036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/14/2020] [Accepted: 08/22/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Adipose-derived stromal/stem cells (ASCs) have multilineage differentiation potential and functional properties, as well as applications for cell-based therapies in tissue repair and regeneration. However, there is a lack of evidence regarding the efficacy of ASCs as an antiobesity agent in aged organisms. This study aimed to clarify the effectiveness of ASCs at treating obesity using a naturally aged mouse model. METHODS Old (22 months) C57BL/6J mice with transplanted young-mice (2 months) donor ASCs were measured for weight change, biochemistry, cytokines, hormone secretion, cell senescence, lipid metabolism, and functional changes of ASCs. RESULTS The results indicated that old mice treated with ASCs showed antiaging and antiobesity effects such as significant loss of body and organ weight, improved stem cell plasticity, increased antioxidant capacity (superoxide dismutase and catalase), improved liver and kidney function, improved lipid metabolism, and increased hormone secretion (sex hormone-binding globulin, thyrotropin, and leptin). Treatment with ASCs decreased cell senescence and suppressed secretion of inflammatory agents (interleukin-6 and tumor necrosis factor alpha). CONCLUSIONS Traditional drugs used in the treatment of obesity have limitations and are unsuitable for the elderly. Based on the results, the future use of ASCs as primary antiaging and antiobesity agents is suggested because of their positive effects on aged animals.
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Affiliation(s)
- Qiong Wu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Shuangli He
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Yu Zhu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Shiming Pu
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
| | - Zuping Zhou
- School of Life Sciences, Guangxi Normal University, Guilin, China
- Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, China
- Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, China
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26
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Ohta H, Liu X, Maeda M. Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study. Stem Cell Res Ther 2020; 11:538. [PMID: 33308301 PMCID: PMC7733281 DOI: 10.1186/s13287-020-02067-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 10/21/2020] [Indexed: 12/18/2022] Open
Abstract
Objective Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis. Methods We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients’ characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared. Results Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment. Conclusions These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.
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Affiliation(s)
- Hiroki Ohta
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
| | - Xiaolan Liu
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Miho Maeda
- Regenerative Medicine, Sun Field Clinic, TIME24 Building 1F 2-4-32 Aomi, Koto-ku, Tokyo, 135-0064, Japan
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Adipose-Derived Stem Cells: Current Applications and Future Directions in the Regeneration of Multiple Tissues. Stem Cells Int 2020; 2020:8810813. [PMID: 33488736 PMCID: PMC7787857 DOI: 10.1155/2020/8810813] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/04/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ADSCs) can maintain self-renewal and enhanced multidifferentiation potential through the release of a variety of paracrine factors and extracellular vesicles, allowing them to repair damaged organs and tissues. Consequently, considerable attention has increasingly been paid to their application in tissue engineering and organ regeneration. Here, we provide a comprehensive overview of the current status of ADSC preparation, including harvesting, isolation, and identification. The advances in preclinical and clinical evidence-based ADSC therapy for bone, cartilage, myocardium, liver, and nervous system regeneration as well as skin wound healing are also summarized. Notably, the perspectives, potential challenges, and future directions for ADSC-related researches are discussed. We hope that this review can provide comprehensive and standardized guidelines for the safe and effective application of ADSCs to achieve predictable and desired therapeutic effects.
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De Bleye C, Fontaine M, Dumont E, Sacré PY, Hubert P, Theys N, Ziemons E. Raman imaging as a new analytical tool for the quality control of the monitoring of osteogenic differentiation in forming 3D bone tissue. J Pharm Biomed Anal 2020; 186:113319. [PMID: 32361470 DOI: 10.1016/j.jpba.2020.113319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/09/2020] [Accepted: 04/15/2020] [Indexed: 12/20/2022]
Abstract
In this study, adipose-derived stem cells (ASCs) are used to produce 3D bone grafts. The safety and the feasibility of using these bone grafts have been already showed and quality controls are already implemented. However, a cheaper, fast and non-destructive technique is required to monitor the osteogenic differentiation process. Here, the use of Raman imaging to monitor the synthesis of the extracellular matrix and its progressive mineralization occurring during the osteogenic differentiation process is investigated for the first time on a 3D in forming bone tissue. The attention was focused on Raman bands related to this matrix belonging to phosphate, phenylalanine and hydroxyproline, which are very distinctive and intense. The kinetic of the osteogenic differentiation process was first compared between a 2D and a 3D forming bone tissue. It was observed that the kinetics of the osteogenic differentiation process is slower in 3D in forming bone tissue. In a second step, an evaluation of the reliability of the Raman imaging method was performed including a study of the influence of the harvest biopsies position on the forming 3D bone tissue. The repeatability and the specificity of this method were also demonstrated. In a last step, several batches of ASCs were cultured and analyzed in 3D at different time points using Raman imaging. From the mean Raman spectra, mineral to matrix ratios (MTMR) were determined and used to evaluate the formation of mineral deposits accompanying the extracellular matrix synthesis which is indicative of an ongoing osteogenic differentiation process. These ratios peaked between the day 35 and 49. This observation was very interesting since it corresponds to the time at which the 3D bone grafts are used for the patient surgery. To conclude, Raman imaging allowed fast acquisition and time-resolved monitoring in vitro of the mineralization of extracellular matrix during osteogenic differentiation.
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Affiliation(s)
- C De Bleye
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium.
| | - M Fontaine
- Novadip Biosciences, Rue Grandbonpré 11, 1435 Mont-Saint-Guibert, Belgium
| | - E Dumont
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - P-Y Sacré
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - Ph Hubert
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - N Theys
- Novadip Biosciences, Rue Grandbonpré 11, 1435 Mont-Saint-Guibert, Belgium
| | - E Ziemons
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
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Piejko M, Radziun K, Bobis-Wozowicz S, Waligórska A, Zimoląg E, Nessler M, Chrapusta A, Madeja Z, Drukała J. Adipose-Derived Stromal Cells Seeded on Integra ® Dermal Regeneration Template Improve Post-Burn Wound Reconstruction. Bioengineering (Basel) 2020; 7:bioengineering7030067. [PMID: 32630660 PMCID: PMC7552717 DOI: 10.3390/bioengineering7030067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/29/2022] Open
Abstract
Fibrosis of burn-related wounds remains an unresolved clinical issue that leads to patient disability. The aim of this study was to assess the efficacy of the transplantation of adipose-derived stromal cells seeded onto a collagen-based matrix in the reconstruction of burn-related scars. Here, we characterized an in vitro interaction between adipose-derived stromal cells and a collagen-based matrix, Integra®DRT. Our results show that transcription of pro-angiogenic, remodeling, and immunomodulatory factors was more significant in adipose-derived stromal cells than in fibroblasts. Transcription of metalloproteinases 2 and 9 is positively correlated with the collagenolytic activity of the adipose-derived stromal cells seeded onto Integra®DRT. The increase in the enzymatic activity corresponds to the decrease in the elasticity of the whole construct. Finally, we validated the treatment of a post-excision wound using adipose-derived stromal cells and an Integra®DRT construct in a 25-year-old woman suffering from burn-related scars. Scarless healing was observed in the area treated by adipose-derived stromal cells and the Integra®DRT construct but not in the reference area where Integra®DRT was applied without cells. This clinical observation may be explained by in vitro findings: Enhanced transcription of the vascular endothelial growth factor as well as remodeling of the collagen-based matrix decreased mechanical stress. Our experimental treatment demonstrated that the adipose-derived stromal cells seeded onto Integra®DRT exhibit valuable properties that may improve post-excision wound healing and facilitate skin regeneration without scars.
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Affiliation(s)
- Marcin Piejko
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
- Department of General Surgery, Jagiellonian University Medical College, 31-215 Krakow, Poland
| | - Karolina Radziun
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
| | - Sylwia Bobis-Wozowicz
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
| | - Agnieszka Waligórska
- Department of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
| | - Eliza Zimoląg
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
| | - Michał Nessler
- Malopolska Center for Burns and Plastic Surgery, The Ludwik Rydygier Hospital, 31-826 Krakow, Poland; (M.N.); (A.C.)
| | - Anna Chrapusta
- Malopolska Center for Burns and Plastic Surgery, The Ludwik Rydygier Hospital, 31-826 Krakow, Poland; (M.N.); (A.C.)
| | - Zbigniew Madeja
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
| | - Justyna Drukała
- Cell Bank, Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.P.); (K.R.); (S.B.-W.); (E.Z.); (Z.M.)
- Correspondence:
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Integrin β1 in Adipose-Derived Stem Cells Accelerates Wound Healing via Activating PI3K/AKT Pathway. Tissue Eng Regen Med 2020; 17:183-192. [PMID: 32200515 DOI: 10.1007/s13770-019-00229-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 10/27/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND This study aims to investigate the effect of integrin β1 on wound healing induced by adipose-derived stem cells (ADSCs), as well as the corresponding mechanism. METHODS Integrin β1 was overexpressed in ADSCs. Thereafter, flow cytometry and transwell chambers technology were used to measure the endothelial-like differentiation (CD31 as a biomarker of endothelial cell) and cell migration, respectively. Western blot was used to detect the activation of PI3K/AKT, NF-κB and ERK signaling pathways. The effects of integrin β1 overexpression on healing time, healing rate and fibroblast number were further evaluated in the rat models of chronic refractory wound. RESULTS The overexpression of integrin β1 increased CD31+ endothelial-like cells (about 3.6-fold), promoted cell migration (about 1.9-fold) and enhanced the activation of PI3K (p-PI3K; about 2.1-fold) and AKT (p-AKT; about 2.2-fold). These effects were all weakened when PI3K/AKT pathway was inhibited by LY294002 treatment. In addition, the experiments in rat wound models showed that integrin β1 overexpression obviously shortened healing time (approximately 0.41-fold), increased healing rate (about 2.7-fold, 2.8-fold and 1.6-fold at day 7, 14 and 21) and increased the number of fibroblasts (approximately 3.1-fold at day 21). All of the above differences were statistically significant (p < 0.05). CONCLUSION Integrin β1 can promote the migration and endothelial-like differentiation of ADSCs by activating PI3K/AKT pathway and then enhance the function of ADSCs in promoting wound healing.
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Ahmadzadeh N, Robering JW, Kengelbach-Weigand A, Al-Abboodi M, Beier JP, Horch RE, Boos AM. Human adipose-derived stem cells support lymphangiogenesis in vitro by secretion of lymphangiogenic factors. Exp Cell Res 2020; 388:111816. [PMID: 31923426 DOI: 10.1016/j.yexcr.2020.111816] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/22/2019] [Accepted: 01/03/2020] [Indexed: 02/07/2023]
Abstract
Lymphedema is a chronic progressive disease ultimately resulting in severe, disfiguring swelling and permanent changes of the affected tissues. Presently, there is no causal treatment approach of lymphedema. Therefore, most therapies are purely symptomatic. However, the recent use of stem cell-based therapies has offered new prospects for alternative treatment options. The present study was performed to investigate the effects of human adipose-derived stem cells (ADSCs) on human dermal lymphatic endothelial cells (HDLECs) in terms of basic in vitro lymphangiogenic assays (WST-8 assay, scratch assay, transmigration assay, sprouting assay, tube formation assay). The influence of ADSC-conditioned medium (ADSC-CM) on HDLECs was compared to recombinant VEGF-C, bFGF and HGF. Further ADSC-CM was characterized by protein microarray and enzyme-linked immunosorbent assay (ELISA). Although key-lymphangiogenic growth factors - like VEGF-C - could only be detected in low concentrations within the conditioned medium (CM), HDLECs were potently stimulated to proliferate, migrate and to form tube like structures by ADSC-CM. Despite concentrations more than hundredfold higher than those found in the conditioned medium, stimulation with recombinant VEGF-C, bFGF and HGF was still weaker compared to ADSC-CM. These results highlight the effectiveness of growth factors secreted by ADSC to stimulate HDLEC, potentially providing a promising new therapeutic approach for the treatment of lymphedema.
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Affiliation(s)
- Nima Ahmadzadeh
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany
| | - Jan W Robering
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany; Department of Plastic Surgery, Hand Surgery, Burns Center, University Hospital RWTH Aachen University, University Hospital Aachen, Germany
| | - Annika Kengelbach-Weigand
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany
| | - Majida Al-Abboodi
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany; Institute of Genetic Engineering and Biotechnology, University of Baghdad, Iraq
| | - Justus P Beier
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany; Department of Plastic Surgery, Hand Surgery, Burns Center, University Hospital RWTH Aachen University, University Hospital Aachen, Germany
| | - Raymund E Horch
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany
| | - Anja M Boos
- Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Germany; Department of Plastic Surgery, Hand Surgery, Burns Center, University Hospital RWTH Aachen University, University Hospital Aachen, Germany.
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Adipose-Derived Stem Cells in Bone Tissue Engineering: Useful Tools with New Applications. Stem Cells Int 2019; 2019:3673857. [PMID: 31781238 PMCID: PMC6875209 DOI: 10.1155/2019/3673857] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
Adipose stem cells (ASCs) are a crucial element in bone tissue engineering (BTE). They are easy to harvest and isolate, and they are available in significative quantities, thus offering a feasible and valid alternative to other sources of mesenchymal stem cells (MSCs), like bone marrow. Together with an advantageous proliferative and differentiative profile, they also offer a high paracrine activity through the secretion of several bioactive molecules (such as growth factors and miRNAs) via a sustained exosomal release which can exert efficient conditioning on the surrounding microenvironment. BTE relies on three key elements: (1) scaffold, (2) osteoprogenitor cells, and (3) bioactive factors. These elements have been thoroughly investigated over the years. The use of ASCs has offered significative new advancements in the efficacy of each of these elements. Notably, the phenotypic study of ASCs allowed discovering cell subpopulations, which have enhanced osteogenic and vasculogenic capacity. ASCs favored a better vascularization and integration of the scaffolds, while improvements in scaffolds' materials and design tried to exploit the osteogenic features of ASCs, thus reducing the need for external bioactive factors. At the same time, ASCs proved to be an incredible source of bioactive, proosteogenic factors that are released through their abundant exosome secretion. ASC exosomes can exert significant paracrine effects in the surroundings, even in the absence of the primary cells. These paracrine signals recruit progenitor cells from the host tissues and enhance regeneration. In this review, we will focus on the recent discoveries which have involved the use of ASCs in BTE. In particular, we are going to analyze the different ASCs' subpopulations, the interaction between ASCs and scaffolds, and the bioactive factors which are secreted by ASCs or can induce their osteogenic commitment. All these advancements are ultimately intended for a faster translational and clinical application of BTE.
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Gentile P, Calabrese C, De Angelis B, Pizzicannella J, Kothari A, Garcovich S. Impact of the Different Preparation Methods to Obtain Human Adipose-Derived Stromal Vascular Fraction Cells (AD-SVFs) and Human Adipose-Derived Mesenchymal Stem Cells (AD-MSCs): Enzymatic Digestion Versus Mechanical Centrifugation. Int J Mol Sci 2019; 20:5471. [PMID: 31684107 PMCID: PMC6862236 DOI: 10.3390/ijms20215471] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/27/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022] Open
Abstract
Autologous therapies using adipose-derived stromal vascular fraction (AD-SVFs) and adult adipose-derived mesenchymal stem cells (AD-MSCs) warrant careful preparation of the harvested adipose tissue. Currently, no standardized technique for this preparation exists. Processing quantitative standards (PQSs) define manufacturing quantitative variables (such as time, volume, and pressure). Processing qualitative standards (PQLSs) define the quality of the materials and methods in manufacturing. The purpose of the review was to use PQSs and PQLSs to report the in vivo and in vitro results obtained by different processing kits that use different procedures (enzymatic vs. non-enzymatic) to isolate human AD-SVFs/AD-MSCs. PQSs included the volume of fat tissue harvested and reagents used, the time/gravity of centrifugation, and the time, temperature, and tilt level/speed of incubation and/or centrifugation. PQLSs included the use of a collagenase, a processing time of 30 min, kit weight, transparency of the kit components, the maintenance of a closed sterile processing environment, and the use of a small centrifuge and incubating rocker. Using a kit with the PQSs and PQLSs described in this study enables the isolation of AD-MSCs that meet the consensus quality criteria. As the discovery of new critical quality attributes (CQAs) of AD-MSCs evolve with respect to purity and potency, adjustments to these benchmark PQSs and PQLs will hopefully isolate AD-MSCs of various CQAs with greater reproducibility, quality, and safety. Confirmatory studies will no doubt need to be completed.
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Affiliation(s)
- Pietro Gentile
- Surgical Science Department, Plastic and Reconstructive Surgery, University of Rome "Tor Vergata", 00179 Rome, Italy.
| | | | - Barbara De Angelis
- Surgical Science Department, Plastic and Reconstructive Surgery, University of Rome "Tor Vergata", 00179 Rome, Italy.
| | | | - Ashutosh Kothari
- Chief of Breast Surgery Unit, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK.
| | - Simone Garcovich
- Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
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Gao Y, Ku NJ, Sung TC, Higuchi A, Hung CS, Lee HHC, Ling QD, Cheng NC, Umezawa A, Barro L, Burnouf T, Ye Q, Chen H. The effect of human platelet lysate on the differentiation ability of human adipose-derived stem cells cultured on ECM-coated surfaces. J Mater Chem B 2019; 7:7110-7119. [PMID: 31513217 DOI: 10.1039/c9tb01764j] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Human mesenchymal stem cells (hMSCs), such as human adipose-derived stem cells (hADSCs), present heterogeneous characteristics, including varying differentiation abilities and genotypes. hADSCs isolated under different conditions exhibit differences in stemness. We isolated hADSCs from human fat tissues via culture on different cell culture biomaterials including tissue culture polystyrene (TCPS) dishes and extracellular matrix protein (ECM)-coated dishes in medium supplemented with 5% or 10% serum-converted human platelet lysate (hPL) or 10% fetal bovine serum (FBS) as a control. Currently, it is not clear whether xeno-free hPL in the cell culture medium promotes the ability of hMSCs such as hADSCs to differentiate into several cell lineages compared to the xenomaterial FBS. We investigated whether a synchronized effect of ECM (Matrigel, fibronectin, and recombinant vitronectin) coatings on TCPS dishes for efficient hADSC differentiation could be observed when hADSCs were cultured in hPL medium. We found that Matrigel-coated dishes promoted hADSC differentiation into osteoblasts and suppressed differentiation into chondrocytes in 10% hPL medium. Recombinant vitronectin- and fibronectin-coated dishes greatly promoted hADSC differentiation into osteoblasts and chondrocytes in 5% and 10% hPL media. hPL promoted hADSC differentiation into osteoblasts and chondrocytes compared to FBS on the fibronectin-coated surface and recombinant vitronectin-coated surface.
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Affiliation(s)
- Yan Gao
- School of Biomedical Engineering, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang 325027, China.
| | - Nien-Ju Ku
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd, Jhongli, Taoyuan 32001, Taiwan
| | - Tzu-Cheng Sung
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd, Jhongli, Taoyuan 32001, Taiwan
| | - Akon Higuchi
- School of Biomedical Engineering, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang 325027, China. and Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd, Jhongli, Taoyuan 32001, Taiwan and Center for Emergent Matter Science, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan and Wenzhou Institute, University of Chinese Academy of Science, No. 16, Xinsan Road, Hi-Tech Industry Park, Wenzhou, Zhejiang, China
| | - Chi-Sheng Hung
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda Rd, Jhongli, Taoyuan 32001, Taiwan
| | - Henry Hsin-Chung Lee
- Department of Surgery, Hsinchu Cathay General Hospital, No. 678, Sec 2, Zhonghua Rd, Hsinchu, 30060, Taiwan and Graduate Institute of Translational and Interdisciplinary Medicine, National Central University, No. 300, Jhongda Rd, Jhongli, Taoyuan 32001, Taiwan
| | - Qing-Dong Ling
- Cathay Medical Research Institute, Cathay General Hospital, No. 32, Ln 160, Jian-Cheng Road, Hsi-Chi City, Taipei 221, Taiwan
| | - Nai-Chen Cheng
- Department of Surgery, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan S. Rd, Taipei 100, Taiwan
| | - Akihiro Umezawa
- Department of Reproduction, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
| | - Lassina Barro
- International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, No. 250 Wu-Xing Street, Taipei 11031, Taiwan
| | - Thierry Burnouf
- International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, No. 250 Wu-Xing Street, Taipei 11031, Taiwan and Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, No. 250 Wu-Xing Street, Taipei 11031, Taiwan
| | - Qingsong Ye
- Regenerative Dentistry Group, School of Dentistry, The University of Queensland, 288 Herston Road, Herston Qld, Brisbane 4006, Australia
| | - Hao Chen
- School of Biomedical Engineering, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang 325027, China.
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Bone allografts combined with adipose-derived stem cells in an optimized cell/volume ratio showed enhanced osteogenesis and angiogenesis in a murine femur defect model. J Mol Med (Berl) 2019; 97:1439-1450. [PMID: 31367858 DOI: 10.1007/s00109-019-01822-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 07/02/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
Critical sized defects, especially in long bones, pose one of the biggest problems in orthopedic surgery. By definition, these defects do not heal without further treatment. Different therapeutic options range from autologous bone grafts, for example, free vascularized bone grafts, to commercially available bone allografts. Disadvantages of these bone allografts are related to reduced osteogenesis, since they are solely composed of cell-free bone matrix. The purpose of this study was to investigate the cell seeding efficiency of human adipose-derived stem cells (hASCs) on human bone allografts in vitro and furthermore analyze these optimized seeded allografts in a critical sized defect model in vivo. Cancellous human bone allografts were colonized with human ASCs in vitro. Cell seeding efficiency was evaluated by Cell Counting Kit-8 assay. Thereafter, optimized hASC-seeded bone scaffolds were examined in a murine femur defect model, stabilized with the MouseExFix system. Subsequently, x-ray analysis and histology were performed. Examination of cell seeding efficiency revealed an optimum starting population of 84,600 cells per 100 mm3 scaffold. In addition, scaffolds seeded with hASCs showed increased osteogenesis compared with controls. Histological analysis revealed increased remodeling and elevated new bone formation within hASC-seeded scaffolds. Moreover, immunohistochemical stainings revealed increased proliferation, osteogenesis, and angiogenesis. In this study, we systemically optimized cell/volume ratio of two promising components of tissue engineering: hASCs and human bone allografts. These findings may serve as a basis for future translational studies. KEY MESSAGES: Bone tissue engineering. Mesenchymal stem cells derived from human adipose tissue (hASCs). Optimal cell/volume ratio of cell-seeded scaffolds. Increased osteogenesis and angiogenesis in vivo.
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Genetically Engineered-MSC Therapies for Non-unions, Delayed Unions and Critical-size Bone Defects. Int J Mol Sci 2019; 20:ijms20143430. [PMID: 31336890 PMCID: PMC6678255 DOI: 10.3390/ijms20143430] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 12/21/2022] Open
Abstract
The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair.
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Scioli MG, Storti G, D'Amico F, Gentile P, Kim BS, Cervelli V, Orlandi A. Adipose-Derived Stem Cells in Cancer Progression: New Perspectives and Opportunities. Int J Mol Sci 2019; 20:3296. [PMID: 31277510 PMCID: PMC6651808 DOI: 10.3390/ijms20133296] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022] Open
Abstract
Growing importance has been attributed to interactions between tumors, the stromal microenvironment and adult mesenchymal stem cells. Adipose-derived stem cells (ASCs) are routinely employed in regenerative medicine and in autologous fat transfer procedures. To date, clinical trials have failed to demonstrate the potential pro-oncogenic role of ASC enrichment. Nevertheless, some pre-clinical studies from in vitro and in vivo models have suggested that ASCs act as a potential tumor promoter for different cancer cell types, and support tumor progression and invasiveness through the activation of several intracellular signals. Interaction with the tumor microenvironment and extracellular matrix remodeling, the exosomal release of pro-oncogenic factors as well as the induction of epithelial-mesenchymal transitions are the most investigated mechanisms. Moreover, ASCs have also demonstrated an elective tumor homing capacity and this tumor-targeting capacity makes them a suitable carrier for anti-cancer drug delivery. New genetic and applied nanotechnologies may help to design promising anti-cancer cell-based approaches through the release of loaded intracellular nanoparticles. These new anti-cancer therapies can more effectively target tumor cells, reaching higher local concentrations even in pharmacological sanctuaries, and thus minimizing systemic adverse drug effects. The potential interplay between ASCs and tumors and potential ASCs-based therapeutic approaches are discussed.
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Affiliation(s)
- Maria Giovanna Scioli
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Federico D'Amico
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Pietro Gentile
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Bong-Sung Kim
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Augusto Orlandi
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
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Stamatopoulos A, Stamatopoulos T, Gamie Z, Kenanidis E, Ribeiro RDC, Rankin KS, Gerrand C, Dalgarno K, Tsiridis E. Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice. J Bone Oncol 2019; 16:100231. [PMID: 30956944 PMCID: PMC6434099 DOI: 10.1016/j.jbo.2019.100231] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 03/14/2019] [Accepted: 03/18/2019] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Recently, Mesenchymal Stromal Cells (MSCs) have been the subject of significant research in orthopaedic clinical practice through their use in regenerative medicine. Further research has been directed at the use of MSCs for more personalized bone sarcoma treatments, taking advantage of their wide range of potential biological functions, which can be augmented by using tissue engineering approaches to promote healing of large defects. In this review, we explore the use of MSCs in bone sarcoma treatment, by analyzing MSCs and tumour cell interactions, transduction of MSCs to target sarcoma, and their clinical applications on humans concerning bone regeneration after bone sarcoma extraction.
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Key Words
- 5-FC, 5-fluorocytosine
- AAT, a1-antitrypsin
- APCs, antigen presenting cells
- ASC, adipose-derived stromal/stem cells
- Abs, antibodies
- Ang1, angiopoietin-1
- BD, bone defect
- BMMSCs, bone marrow-derived mesenchymal stromal cells
- Biology
- Bone
- CAM, cell adhesion molecules
- CCL5, chemokine ligand 5
- CCR2, chemokine receptor 2
- CD, classification determinants
- CD, cytosine deaminase
- CLUAP1, clusterin associated protein 1
- CSPG4, Chondroitin sulfate proteoglycan 4
- CX3CL1, chemokine (C-X3-C motif) ligand 1
- CXCL12/CXCR4, C-X-C chemokine ligand 12/ C-X-C chemokine receptor 4
- CXCL12/CXCR7, C-X-C chemokine ligand 12/ C-X-C chemokine receptor 7
- CXCR4, chemokine receptor type 4
- Cell
- DBM, Demineralized Bone Marrow
- DKK1, dickkopf-related protein 1
- ECM, extracellular matrix
- EMT, epithelial-mesenchymal transition
- FGF-2, fibroblast growth factors-2
- FGF-7, fibroblast growth factors-7
- GD2, disialoganglioside 2
- HER2, human epidermal growth factor receptor 2
- HGF, hepatocyte growth factor
- HMGB1/RACE, high mobility group box-1 protein/ receptor for advanced glycation end-products
- IDO, indoleamine 2,3-dioxygenase
- IFN-α, interferon alpha
- IFN-β, interferon beta
- IFN-γ, interferon gamma
- IGF-1R, insulin-like growth factor 1 receptor
- IL-10, interleukin-10
- IL-12, interleukin-12
- IL-18, interleukin-18
- IL-1b, interleukin-1b
- IL-21, interleukin-21
- IL-2a, interleukin-2a
- IL-6, interleukin-6
- IL-8, interleukin-8
- IL11RA, Interleukin 11 Receptor Subunit Alpha
- MAGE, melanoma antigen gene
- MCP-1, monocyte chemoattractant protein-1
- MMP-2, matrix metalloproteinase-2
- MMP2/9, matrix metalloproteinase-2/9
- MRP, multidrug resistance protein
- MSCs, mesenchymal stem/stromal cells
- Mesenchymal
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- OPG, osteoprotegerin
- Orthopaedic
- PBS, phosphate-buffered saline
- PDGF, platelet-derived growth factor
- PDX, patient derived xenograft
- PEDF, pigment epithelium-derived factor
- PGE2, prostaglandin E2
- PI3K/Akt, phosphoinositide 3-kinase/protein kinase B
- PTX, paclitaxel
- RANK, receptor activator of nuclear factor kappa-B
- RANKL, receptor activator of nuclear factor kappa-B ligand
- RBCs, red blood cells
- RES, reticuloendothelial system
- RNA, ribonucleic acid
- Regeneration
- SC, stem cells
- SCF, stem cells factor
- SDF-1, stromal cell-derived factor 1
- STAT-3, signal transducer and activator of transcription 3
- Sarcoma
- Stromal
- TAAs, tumour-associated antigens
- TCR, T cell receptor
- TGF-b, transforming growth factor beta
- TGF-b1, transforming growth factor beta 1
- TNF, tumour necrosis factor
- TNF-a, tumour necrosis factor alpha
- TRAIL, tumour necrosis factor related apoptosis-inducing ligand
- Tissue
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- WBCs, white blood cell
- hMSCs, human mesenchymal stromal cells
- rh-TRAIL, recombinant human tumour necrosis factor related apoptosis-inducing ligand
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Affiliation(s)
- Alexandros Stamatopoulos
- Academic Orthopaedic Unit, Papageorgiou General Hospital, Aristotle University Medical School, West Ring Road of Thessaloniki, Pavlos Melas Area, N. Efkarpia, 56403 Thessaloniki, Greece
- Center of Orthopaedics and Regenerative Medicine (C.O.RE.), Center for Interdisciplinary Research and Innovation (C.I.R.I.), Aristotle University Thessaloniki, Greece
| | - Theodosios Stamatopoulos
- Academic Orthopaedic Unit, Papageorgiou General Hospital, Aristotle University Medical School, West Ring Road of Thessaloniki, Pavlos Melas Area, N. Efkarpia, 56403 Thessaloniki, Greece
- Center of Orthopaedics and Regenerative Medicine (C.O.RE.), Center for Interdisciplinary Research and Innovation (C.I.R.I.), Aristotle University Thessaloniki, Greece
| | - Zakareya Gamie
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Eustathios Kenanidis
- Academic Orthopaedic Unit, Papageorgiou General Hospital, Aristotle University Medical School, West Ring Road of Thessaloniki, Pavlos Melas Area, N. Efkarpia, 56403 Thessaloniki, Greece
- Center of Orthopaedics and Regenerative Medicine (C.O.RE.), Center for Interdisciplinary Research and Innovation (C.I.R.I.), Aristotle University Thessaloniki, Greece
| | - Ricardo Da Conceicao Ribeiro
- School of Mechanical and Systems Engineering, Stephenson Building, Claremont Road, Newcastle upon Tyne NE1 7RU, UK
| | - Kenneth Samora Rankin
- Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Craig Gerrand
- Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, HA7 4LP, UK
| | - Kenneth Dalgarno
- School of Mechanical and Systems Engineering, Stephenson Building, Claremont Road, Newcastle upon Tyne NE1 7RU, UK
| | - Eleftherios Tsiridis
- Academic Orthopaedic Unit, Papageorgiou General Hospital, Aristotle University Medical School, West Ring Road of Thessaloniki, Pavlos Melas Area, N. Efkarpia, 56403 Thessaloniki, Greece
- Center of Orthopaedics and Regenerative Medicine (C.O.RE.), Center for Interdisciplinary Research and Innovation (C.I.R.I.), Aristotle University Thessaloniki, Greece
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Yamazaki T, Kishimoto T, Leszczyński P, Sadakane K, Kenmotsu T, Watanabe H, Kazama T, Matsumoto T, Yoshikawa K, Taniguchi H. Construction of 3D Cellular Composites with Stem Cells Derived from Adipose Tissue and Endothelial Cells by Use of Optical Tweezers in a Natural Polymer Solution. MATERIALS 2019; 12:ma12111759. [PMID: 31151204 PMCID: PMC6601048 DOI: 10.3390/ma12111759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/17/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023]
Abstract
To better understand the regulation and function of cellular interactions, three-dimensional (3D) assemblies of single cells and subsequent functional analysis are gaining popularity in many research fields. While we have developed strategies to build stable cellular structures using optical tweezers in a minimally invasive state, methods for manipulating a wide range of cell types have yet to be established. To mimic organ-like structures, the construction of 3D cellular assemblies with variety of cell types is essential. Our recent studies have shown that the presence of nonspecific soluble polymers in aqueous solution is the key to creating stable 3D cellular assemblies efficiently. The present study further expands on the construction of 3D single cell assemblies using two different cell types. We have successfully generated 3D cellular assemblies, using GFP-labeled adipose tissue-derived stem cells and endothelial cells by using optical tweezers. Our findings will support the development of future applications to further characterize cellular interactions in tissue regeneration.
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Affiliation(s)
- Takehiro Yamazaki
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
| | - Toshifumi Kishimoto
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
| | - Paweł Leszczyński
- Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland.
| | - Koichiro Sadakane
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
| | - Takahiro Kenmotsu
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
| | - Hirofumi Watanabe
- Department of Functional Morphology, Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo 173-8610, Japan.
| | - Tomohiko Kazama
- Department of Functional Morphology, Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo 173-8610, Japan.
| | - Taro Matsumoto
- Department of Functional Morphology, Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo 173-8610, Japan.
| | - Kenichi Yoshikawa
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan.
| | - Hiroaki Taniguchi
- Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland.
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40
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Neri S. Genetic Stability of Mesenchymal Stromal Cells for Regenerative Medicine Applications: A Fundamental Biosafety Aspect. Int J Mol Sci 2019; 20:ijms20102406. [PMID: 31096604 PMCID: PMC6566307 DOI: 10.3390/ijms20102406] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 05/08/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSC) show widespread application for a variety of clinical conditions; therefore, their use necessitates continuous monitoring of their safety. The risk assessment of mesenchymal stem cell-based therapies cannot be separated from an accurate and deep knowledge of their biological properties and in vitro and in vivo behavior. One of the most relevant safety issues is represented by the genetic stability of MSCs, that can be altered during in vitro manipulation, frequently required before clinical application. MSC genetic stability has the potential to influence the transformation and the therapeutic effect of these cells. At present, karyotype evaluation represents the definitely prevailing assessment of MSC stability, but DNA alterations of smaller size should not be underestimated. This review will focus on current scientific knowledge about the genetic stability of mesenchymal stem cells. The techniques used and possible improvements together with regulatory aspects will also be discussed.
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Affiliation(s)
- Simona Neri
- Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
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Salamanna F, Giavaresi G, Contartese D, Bigi A, Boanini E, Parrilli A, Lolli R, Gasbarrini A, Barbanti Brodano G, Fini M. Effect of strontium substituted ß-TCP associated to mesenchymal stem cells from bone marrow and adipose tissue on spinal fusion in healthy and ovariectomized rat. J Cell Physiol 2019; 234:20046-20056. [PMID: 30950062 DOI: 10.1002/jcp.28601] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/11/2019] [Accepted: 03/19/2019] [Indexed: 01/05/2023]
Abstract
Despite alternatives to autogenous bone graft for spinal fusion have been investigated, it has been shown that osteoconductive materials alone do not give a rate of fusion comparable with autogenous bone. This study analyzed a strontium substituted ß-tricalcium phosphate (Sr-ßTCP) associated with syngeneic, unexpanded, and undifferentiated mesenchymal stem cells from bone marrow (BMSC) or adipose tissue (ADSC) as a new tissue engineering approach for spinal fusion procedures. A posterolateral fusion was performed in 15 ovariectomized (OVX) and 15 sham-operated (SHAM) Inbred rats. Both SHAM and OVX animals were divided into three groups: Sr-ßTCP, Sr-ßTCP + BMCSs, and Sr-ßTCP + ADSCs. Animals were euthanized 8 weeks after surgery and the spines evaluated by manual palpation, micro-CT, and histology. For both SHAM and OVX animals, the fusion tissue in the Sr-ßTCP + BMSCs group was more solid. This effect was significantly higher in OVX animals by comparing the Sr-ßTCP + BMCSs group with Sr-ßTCP + ADSCs. Radiographical score, based on micro-CT 2D image, highlighted that the Sr-ßTCP + BMCSs group presented a similar fusion to Sr-ßTCP and higher than Sr-ßTCP + ADSCs in both SHAM and OVX animals. Micro-CT 3D parameters did not show significant differences among groups. Histological score showed significantly higher fusion in Sr-ßTCP + BMSCs group than Sr-ßTCP and Sr-ßTCP + ADSCs, for both SHAM and OVX animals. In conclusion, our results suggest that addition of BMSCs to a Sr-ßTCP improve bone formation and fusion, both in osteoporotic and nonosteoporotic animal, whereas spinal fusion is not enhanced in rats treated with Sr-ßTCP + ADSCs. Thus, for conducting cells therapy in spinal surgery BMSCs still seems to be a better choice compared with ADSCs.
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Affiliation(s)
- Francesca Salamanna
- Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Gianluca Giavaresi
- Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Deyanira Contartese
- Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Adriana Bigi
- Department of Chemistry "G.Ciamician", University of Bologna, Bologna, Italy
| | - Elisa Boanini
- Department of Chemistry "G.Ciamician", University of Bologna, Bologna, Italy
| | - Annapaola Parrilli
- Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Roberta Lolli
- Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Alessandro Gasbarrini
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Giovanni Barbanti Brodano
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Milena Fini
- Laboratory of Biomechanics and Technological Innovation, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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Grégoire C, Ritacco C, Hannon M, Seidel L, Delens L, Belle L, Dubois S, Vériter S, Lechanteur C, Briquet A, Servais S, Ehx G, Beguin Y, Baron F. Comparison of Mesenchymal Stromal Cells From Different Origins for the Treatment of Graft-vs.-Host-Disease in a Humanized Mouse Model. Front Immunol 2019; 10:619. [PMID: 31001253 PMCID: PMC6454068 DOI: 10.3389/fimmu.2019.00619] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/08/2019] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs failed to demonstrate their superiority over placebo in the sole phase III trial reported thus far. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. Here, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function in vitro and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rγnull HLA-A2/HHD mice. In vitro, resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4+CD25+FoxP3+)/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. In vivo, AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32–1.08, P = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30–1.34, P = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28–1.10, P = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells in vitro and in vivo. However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities in vitro.
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Affiliation(s)
- Céline Grégoire
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
| | - Caroline Ritacco
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Muriel Hannon
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Laurence Seidel
- Department of Biostatistics, SIMÉ, University Hospital Center of Liège, Liège, Belgium
| | - Loïc Delens
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Ludovic Belle
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Sophie Dubois
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Sophie Vériter
- Endocrine Cell Therapy, Centre of Tissue and Cellular Therapy, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Sophie Servais
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
| | - Gregory Ehx
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Yves Beguin
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium.,Laboratory of Cell and Gene Therapy, University Hospital Center and University of Liège, Liège, Belgium
| | - Frédéric Baron
- Hematology Research Unit, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, University Hospital Center of Liège, Liège, Belgium
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43
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Cryopreserved H2
O2
-preconditioned human adipose-derived stem cells exhibit fast post-thaw recovery and enhanced bioactivity against oxidative stress. J Tissue Eng Regen Med 2019; 13:328-341. [DOI: 10.1002/term.2797] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 11/05/2018] [Accepted: 01/09/2019] [Indexed: 12/13/2022]
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44
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Alapure BV, Lu Y, He M, Chu CC, Peng H, Muhale F, Brewerton YL, Bunnell B, Hong S. Accelerate Healing of Severe Burn Wounds by Mouse Bone Marrow Mesenchymal Stem Cell-Seeded Biodegradable Hydrogel Scaffold Synthesized from Arginine-Based Poly(ester amide) and Chitosan. Stem Cells Dev 2018; 27:1605-1620. [PMID: 30215325 PMCID: PMC6276600 DOI: 10.1089/scd.2018.0106] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022] Open
Abstract
Severe burns are some of the most challenging problems in clinics and still lack ideal modalities. Mesenchymal stem cells (MSCs) incorporated with biomaterial coverage of burn wounds may offer a viable solution. In this report, we seeded MSCs to a biodegradable hybrid hydrogel, namely ACgel, that was synthesized from unsaturated arginine-based poly(ester amide) (UArg-PEA) and chitosan derivative. MSC adhered to ACgels. ACgels maintained a high viability of MSCs in culture for 6 days. MSC seeded to ACgels presented well in third-degree burn wounds of mice at 8 days postburn (dpb) after the necrotic full-thickness skin of burn wounds was debrided and filled and covered by MSC-carrying ACgels. MSC-seeded ACgels promoted the closure, reepithelialization, granulation tissue formation, and vascularization of the burn wounds. ACgels alone can also promote vascularization but less effectively compared with MSC-seeded ACgels. The actions of MSC-seeded ACgels or ACgels alone involve the induction of reparative, anti-inflammatory interleukin-10, and M2-like macrophages, as well as the reduction of inflammatory cytokine TNFα and M1-like macrophages at the late inflammatory phase of burn wound healing, which provided the mechanistic insights associated with inflammation and macrophages in burn wounds. For the studied regimens of these treatments, no toxicity was identified to MSCs or mice. Our results indicate that MSC-seeded ACgels have potential use as a novel adjuvant therapy for severe burns to complement commonly used skin grafting and, thus, minimize the downsides of grafting.
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Affiliation(s)
- Bhagwat V. Alapure
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Yan Lu
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Mingyu He
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, New York
| | - Chih-Chang Chu
- Department of Fiber Science and Apparel Design, Cornell University, Ithaca, New York
- Department of Biomedical Engineering, Cornell University, Ithaca, New York
| | - Hongying Peng
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Filipe Muhale
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | | | - Bruce Bunnell
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Song Hong
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana
- Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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45
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Assessment of safety and feasibility of human allogeneic adipose-derived mesenchymal stem cells in a pediatric patient. Pediatr Res 2018; 84:575-577. [PMID: 30140066 DOI: 10.1038/s41390-018-0042-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 04/18/2018] [Indexed: 02/07/2023]
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46
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Hasani S, Boroujeni ME, Aliaghaei A, Baghai K, Rostami A. Dopaminergic induction of human adipose-derived mesenchymal stem cells is accompanied by transcriptional activation of autophagy. Cell Biol Int 2018; 42:1688-1694. [DOI: 10.1002/cbin.11056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 09/16/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Sanaz Hasani
- Faculty of Medical Biotechnology; Department of Stem Cells and Regenerative Medicine; National Institute of Genetic Engineering and Biotechnology; Tehran Iran
| | - Mahdi Eskandarian Boroujeni
- Faculty of Medical Biotechnology; Department of Stem Cells and Regenerative Medicine; National Institute of Genetic Engineering and Biotechnology; Tehran Iran
| | - Abbas Aliaghaei
- Cell Biology and Anatomical Sciences; School of Medicine; Shahid Beheshti University of Medical Sciences; Tehran Iran
| | - Kaveh Baghai
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research center; Research institute for Gastroenterology and Liver Diseases; Shahid Beheshti University of Medical Sciences; Tehran Iran
| | - Amin Rostami
- Gastroenterology and Liver Disease Research Center; Research institute for Gastroenterology and Liver Diseases; Shahid Beheshti University of Medical Sciences; Tehran Iran
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47
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Abstract
Bone nonunion is a pathological condition in which all bone healing processes have stopped, resulting in abnormal mobility between 2 bone segments. The incidence of bone-related injuries will increase in an aging population, leading to such injuries reaching epidemic proportions. Tissue engineering and cell therapy using mesenchymal stem cells (MSCs) have raised the possibility of implanting living tissue for bone reconstruction. Bone marrow was first proposed as the source of stem cells for bone regeneration. However, as the quantity of MSCs in the bone marrow decreases, the capacity of osteogenic differentiation of bone marrow stem cells is also impaired by the donor's age in terms of reduced MSC replicative capacity; an increased number of apoptotic cells; formation of colonies positive for alkaline phosphatase; and decreases in the availability, growth potential, and temporal mobilization of MSCs for bone formation in case of fracture. Adipose-derived stem cells (ASCs) demonstrate several advantages over those from bone marrow, including a less invasive harvesting procedure, a higher number of stem cell progenitors from an equivalent amount of tissue harvested, increased proliferation and differentiation capacities, and better angiogenic and osteogenic properties in vivo. Subcutaneous native adipose tissue was not affected by the donor's age in terms of cellular senescence and yield of ASC isolation. In addition, a constant mRNA level of osteocalcin and alkaline phosphatase with a similar level of matrix mineralization of ASCs remained unaffected by donor age after osteogenic differentiation. The secretome of ASCs was also unaffected by age when aiming to promote angiogenesis by vascular endothelial growth factor (VEGF) release in hypoxic conditions. Therefore, the use of adipose cells for bone tissue engineering is not limited by the donor's age from the isolation of stem cells up to the manufacturing of a complex osteogenic graft.
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Affiliation(s)
- Denis Dufrane
- 1 Novadip Biosciences, Mont-Saint-Guibert, Belgium.,2 Theracell Consulting, Lasne, Belgium
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48
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Bērziņš U, Matise-VanHoutana I, Pētersone I, Dūrītis I, Ņikuļšins S, Bogdanova-Jātniece A, Kālis M, Svirskis Š, Skrastiņa D, Ezerta A, Kozlovska T. Characterisation and In Vivo Safety of Canine Adipose-Derived Stem Cells. PROCEEDINGS OF THE LATVIAN ACADEMY OF SCIENCES. SECTION B. NATURAL, EXACT, AND APPLIED SCIENCES. 2018; 72:160-171. [DOI: 10.2478/prolas-2018-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Abstract
The study characterises canine adipose-derived stem cells (cASCs) in comparison to human ASCs (hASCs) and tests their safety in a canine model after intravenous administration. cASCs from two dogs were cultured under hypoxic conditions in a medium supplemented with autologous serum. They were plastic adherent, spindle-shaped cells that expressed CD73, CD90, and CD44 but lacked CD45, CD14, HLA-DR, and CD34. cASCs differentiated toward adipogenic, osteogenic, and chondrogenic lineages, although adipogenic differentiation capacity was low. Blast transformation reaction demonstrated that these cells significantly suppress T-cell proliferation, and this ability is dose-dependent. Intravenous administration of a cell freezing medium, therapeutic dose of cASCs (2 × 106 live cells/kg), and five times higher dose of cASCs showed no significant side effects in two dogs. Microscopic tissue lesions were limited to only mild, non-specific changes. There were no signs of malignancy. The results of the study indicate that cASCs are similar to hASCs and are safe for therapeutic applications in a canine model. The proposed methodology for ASC preparation on a non-routine basis, which includes individually optimised cell culture conditions and offers risk-adapted treatment, could be used for future personalised off-the-shelf therapies, for example, in myocardial infarction or stroke.
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Affiliation(s)
- Uldis Bērziņš
- Latvian Biomedical Research and Study Centre , 1 Rātsupītes Str., Rīga , LV-1067 , Latvia
- Stem Cells Technologies Ltd. , Rīga , Latvia
| | - Ilze Matise-VanHoutana
- Faculty of Veterinary Medicine , Latvia University of Agriculture , 2 Lielā Str., Jelgava , LV-3001 , Latvia
| | - Ilze Pētersone
- Faculty of Veterinary Medicine , Latvia University of Agriculture , 2 Lielā Str., Jelgava , LV-3001 , Latvia
| | - Ilmārs Dūrītis
- Faculty of Veterinary Medicine , Latvia University of Agriculture , 2 Lielā Str., Jelgava , LV-3001 , Latvia
| | - Sergejs Ņikuļšins
- Children’s Clinical University Hospital , 45 Vienības gatve, Rīga , LV-1004 , Latvia
| | | | - Mārtiņš Kālis
- Augusts Kirhenšteins Institute of Microbiology and Virology , Rīga Stradiņš University , 5 Rātsupītes Str., Rīga , LV-1067 , Latvia
| | - Šimons Svirskis
- Augusts Kirhenšteins Institute of Microbiology and Virology , Rīga Stradiņš University , 5 Rātsupītes Str., Rīga , LV-1067 , Latvia
| | - Dace Skrastiņa
- Latvian Biomedical Research and Study Centre , 1 Rātsupītes Str., Rīga , LV-1067 , Latvia
| | - Agnese Ezerta
- Latvian Biomedical Research and Study Centre , 1 Rātsupītes Str., Rīga , LV-1067 , Latvia
| | - Tatjana Kozlovska
- Latvian Biomedical Research and Study Centre , 1 Rātsupītes Str., Rīga , LV-1067 , Latvia
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49
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Wei ZZ, Zhu YB, Zhang JY, McCrary MR, Wang S, Zhang YB, Yu SP, Wei L. Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy. Chin Med J (Engl) 2018; 130:2361-2374. [PMID: 28937044 PMCID: PMC5634089 DOI: 10.4103/0366-6999.215324] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. Data Sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: “stem cells,” “hypoxic preconditioning,” “ischemic preconditioning,” and “cell transplantation.” Study Selection: Original articles and critical reviews on the topics were selected. Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.
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Affiliation(s)
- Zheng Z Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yan-Bing Zhu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - James Y Zhang
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Myles R McCrary
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Song Wang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yong-Bo Zhang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shan-Ping Yu
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Ling Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University; Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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50
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Xie H, Liao N, Lan F, Cai Z, Liu X, Liu J. 3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition. Int J Mol Med 2018; 41:1385-1396. [PMID: 29286072 PMCID: PMC5819936 DOI: 10.3892/ijmm.2017.3336] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 12/13/2017] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue-derived stem cells (ADSCs) are considered promising candidates for stem cell therapy; however, the tumorigenicity of ADSCs remains controversial. The present study aimed to investigate the association between ADSCs and liver cancer cells, and to determine whether culture methods could influence the effects of ADSCs on liver cancer cell growth in vitro. Liver cancer cells were treated with ADSCs-conditioned medium (CM) that was collected using the two-dimensional (2D) culture method, sphere culture method, or three-dimensional (3D) culture method. After that, cell viability and apoptosis were measured using CCK-8 and Annexin V-FITC assay, respectively; the cell motility and adhesive capacity were analyzed by scratch wound healing and cell adhesion assay, respectively; the cell migration and invasion were examined by Transwell units; and the molecular mechanisms of ADSCs on effecting epithelial mesenchymal transition signaling pathway were further analyzed. The results demonstrated that ADSCs‑CM was able to inhibit the growth of liver cancer cells by inhibiting cell proliferation and promoting cell apoptosis, as well as by suppressing cell motility, adhesive capacity, migration and invasion. In addition, ADSCs‑CM was able to suppress cell growth via the downregulation of epithelial‑mesenchymal transition signaling. Notably, the enhanced inhibitory effects of ADSCs on liver cancer cell growth could be achieved after cultu-ring using a 3D approach. These findings suggested that ADSCs may provide a novel promising therapeutic approach for the treatment of patients with liver cancer, and the 3D culture method may provide a novel approach to explore the association between ADSCs and cancer.
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Affiliation(s)
- Haihua Xie
- Department of Clinical Genetics and Experimental Medicine, Fuzong Clinical College, Fujian Medical University
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025
| | - Fenghua Lan
- Department of Clinical Genetics and Experimental Medicine, Fuzong Clinical College, Fujian Medical University
| | - Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China
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