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Gasanov VAO, Kashirskikh DA, Khotina VA, Lee AA, Nikitochkina SY, Kuzmina DM, Mukhina IV, Vorotelyak EA, Vasiliev AV. Genetically Modified Mesenchymal Stromal/Stem Cells as a Delivery Platform for SE-33, a Cathelicidin LL-37 Analogue: Preclinical Pharmacokinetics and Tissue Distribution in C57BL/6 Mice. Antibiotics (Basel) 2025; 14:429. [PMID: 40426496 PMCID: PMC12108424 DOI: 10.3390/antibiotics14050429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/18/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND The genetic modification of mesenchymal stromal/stem cells (MSCs) to express antimicrobial peptides may provide a promising strategy for developing advanced cell-based therapies for bacterial infections, including those caused or complicated by antibiotic-resistant bacteria. We have previously demonstrated that genetically modified Wharton's jelly-derived MSCs expressing an antimicrobial peptide SE-33 (WJ-MSC-SE33) effectively reduce bacterial load, inflammation, and mortality in a mouse model of Staphylococcus aureus-induced pneumonia compared with native WJ-MSCs. The present study aimed to evaluate the pharmacokinetics and tissue distribution of the SE-33 peptide expressed by WJ-MSC-SE33 following administration to animals. METHODS WJ-MSC-SE33 were administered to C57BL/6 mice at therapeutic and excess doses. The biodistribution and pharmacokinetics of the SE-33 peptide were analyzed in serum, lungs, liver, and spleen using chromatographic methods after single and repeated administrations. RESULTS The SE-33 peptide exhibited dose-dependent pharmacokinetics. The highest levels of SE-33 peptide were detected in the liver and lungs, with persistence in tissues for up to 48 h at medium and high doses of administered WJ-MSC-SE33. A repeated administration of WJ-MSC-SE33 increased SE-33 levels in target organs. CONCLUSIONS The SE-33 peptide expressed by genetically modified WJ-MSCs demonstrated predictable pharmacokinetics and effective biodistribution. These findings, together with the previously established safety profile of WJ-MSC-SE33, support its potential as a promising cell-based therapy for bacterial infections, particularly those associated with antibiotic resistance.
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Affiliation(s)
- Vagif Ali oglu Gasanov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia
| | | | | | - Arthur Anatolievich Lee
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia
| | | | - Daria Mikhailovna Kuzmina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia
| | - Irina Vasilievna Mukhina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia
| | - Ekaterina Andreevna Vorotelyak
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia
- Department of Cell Biology, Biological Faculty, Lomonosov Moscow State University, Moscow 119234, Russia
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Iwai T, Ikeguchi R, Aoyama T, Noguchi T, Yoshimoto K, Sakamoto D, Fujita K, Miyazaki Y, Akieda S, Nagamura-Inoue T, Nagamura F, Nakayama K, Matsuda S. Nerve regeneration using a Bio 3D conduit derived from umbilical cord-Derived mesenchymal stem cells in a rat sciatic nerve defect model. PLoS One 2024; 19:e0310711. [PMID: 39715170 DOI: 10.1371/journal.pone.0310711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 09/05/2024] [Indexed: 12/25/2024] Open
Abstract
Human umbilical cord-derived mesenchymal stromal cells (UC-MSCs), which can be prepared in advance and are presumed to be advantageous for nerve regeneration, have potential as a cell source for Bio 3D conduits. The purpose of this study was to evaluate the nerve regeneration ability of Bio 3D conduits made from UC-MSCs using a rat sciatic nerve defect model. METHODS A Bio 3D conduit was fabricated using a Bio 3D printer by placing UC-MSC spheroids into thin needles according to predesigned 3D data. The conduit was transplanted to bridge the 5-mm gaps of Lewis rat sciatic nerve, and nerve regeneration was evaluated at 8 weeks (Bio 3D group). Transplantation of autologous nerve segments (autograft) and silicone tubes represented the positive and negative control groups, respectively. In a second experiment, immunological reactions were evaluated in Bio 3D, autograft, and allograft groups by histochemical staining of transplanted segments in Brown Norway rats. RESULTS The mean angle of attack value in the kinematic analysis was significantly better in the Bio 3D group (‒20.1 ± 0.5°) than in the silicone group (‒33.7 ± 1.5°) 8 weeks after surgery. The average diameters of myelinated axons were significantly larger in the Bio 3D group (3.61 ± 0.15 μm) than in the silicone group (3.07 ± 0.12 μm), and the number of myelinated axons was significantly higher in the Bio 3D group (11,201 ± 980) than in the silicone group (8117 ± 646). Histological findings (hematoxylin and eosin [HE] staining and anti-CD3 fluorescent immunostaining) showed that rejection was suppressed in the Bio 3D group compared to the allograft group. Based on macroscopic findings and histological findings (anti-human mitochondrial fluorescent immunostaining), UC-MSCs in the Bio 3D conduit disappeared gradually from week 1 to week 8. CONCLUSIONS The Bio 3D conduit prepared from UC-MSCs was superior to the silicone tube and achieved comparable nerve regeneration to the autologous (autograft) group. Rejection was suppressed in the Bio 3D group compared to the allograft group. Although this study used a xenograft model, we speculate that rejection was low due to the characteristics of UC-MSCs. UC-MSCs are a useful cell source for Bio 3D conduits.
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Affiliation(s)
- Terunobu Iwai
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
| | - Ryosuke Ikeguchi
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
- Department of Rehabilitation Medicine, Kyoto University, Kyoto, Japan
| | - Tomoki Aoyama
- Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Noguchi
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
| | - Koichi Yoshimoto
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
| | - Daichi Sakamoto
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
| | - Kazuaki Fujita
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
| | | | | | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, IMSUT CORD, Research Hospital, The University of Tokyo, Tokyo, Japan
| | - Fumitaka Nagamura
- Division of Advanced Medicine Promotion, The Advanced Clinical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Nakayama
- Department of Regenerative Medicine and Biomedical Engineering, Faculty of Medicine, Saga University, Saga, Japan
| | - Shuichi Matsuda
- Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan
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Ji X, Wang L, Zhong Y, Xu Q, Yan J, Pan D, Xu Y, Chen C, Wang J, Wang G, Yang M, Li T, Tang L, Wang X. Impact of mesenchymal stem cell size and adhesion modulation on in vivo distribution: insights from quantitative PET imaging. Stem Cell Res Ther 2024; 15:456. [PMID: 39609885 PMCID: PMC11606219 DOI: 10.1186/s13287-024-04078-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 11/22/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Successful engraftment and localization of mesenchymal stem cells (MSCs) within target tissues are critical factors influencing their therapeutic efficacy for tissue repair and regeneration. However, the relative contributions of biophysical factors like cell size and adhesion capacity in regulating MSC distribution in vivo remain incompletely understood. METHODS Cell adhesion peptides and hanging drop method were used to modify the adhesive capacity and size of MSCs. To quantitatively track the real-time biodistribution of transplanted MSCs with defined size and adhesion profiles in living mice and rats, the non-invasive positron emission tomography (PET) imaging was applied. RESULTS Surface modification with integrin binding peptides like RGD, GFOGER, and HAVDI reduced MSC adhesion capacity in vitro by up to 43.5% without altering cell size, but did not significantly decrease lung entrapment in vivo. In contrast, culturing MSCs as 3D spheroids for 48 h reduced their cell diameter by 34.6% and markedly enhanced their ability to pass through the lungs and migrate to other organs like the liver after intravenous administration. This size-dependent effect on MSC distribution was more pronounced in rats compared to mice, likely due to differences in pulmonary microvessel diameters between species. CONCLUSION Our findings reveal that cell size is a predominant biophysical regulator of MSC localization in vivo compared to adhesion capacity, providing crucial insights to guide optimization of MSC delivery strategies for enhanced therapeutic efficacy.
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Affiliation(s)
- Xin Ji
- Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, P.R. China
| | - Lizhen Wang
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Yudan Zhong
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Qian Xu
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Junjie Yan
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Donghui Pan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Yuping Xu
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Chongyang Chen
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Jing Wang
- Jiangsu Renocell Biotech Co., Ltd., Nanjing, 211100, P.R. China
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, P.R. China
| | - Min Yang
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China
| | - Tiannv Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, P.R. China
| | - Lijun Tang
- Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, P.R. China.
| | - Xinyu Wang
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, P.R. China.
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P.R. China.
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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Baig MS, Ahmad A, Pathan RR, Mishra RK. Precision Nanomedicine with Bio-Inspired Nanosystems: Recent Trends and Challenges in Mesenchymal Stem Cells Membrane-Coated Bioengineered Nanocarriers in Targeted Nanotherapeutics. J Xenobiot 2024; 14:827-872. [PMID: 39051343 PMCID: PMC11270309 DOI: 10.3390/jox14030047] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/09/2024] [Accepted: 06/15/2024] [Indexed: 07/27/2024] Open
Abstract
In the recent past, the formulation and development of nanocarriers has been elaborated into the broader fields and opened various avenues in their preclinical and clinical applications. In particular, the cellular membrane-based nanoformulations have been formulated to surpass and surmount the limitations and restrictions associated with naïve or free forms of therapeutic compounds and circumvent various physicochemical and immunological barriers including but not limited to systemic barriers, microenvironmental roadblocks, and other cellular or subcellular hinderances-which are quite heterogeneous throughout the diseases and patient cohorts. These limitations in drug delivery have been overcome through mesenchymal cells membrane-based precision therapeutics, where these interventions have led to the significant enhancements in therapeutic efficacies. However, the formulation and development of nanocarriers still focuses on optimization of drug delivery paradigms with a one-size-fits-all resolutions. As mesenchymal stem cell membrane-based nanocarriers have been engineered in highly diversified fashions, these are being optimized for delivering the drug payloads in more and better personalized modes, entering the arena of precision as well as personalized nanomedicine. In this Review, we have included some of the advanced nanocarriers which have been designed and been utilized in both the non-personalized as well as precision applicability which can be employed for the improvements in precision nanotherapeutics. In the present report, authors have focused on various other aspects of the advancements in stem cells membrane-based nanoparticle conceptions which can surmount several roadblocks and barriers in drug delivery and nanomedicine. It has been suggested that well-informed designing of these nanocarriers will lead to appreciable improvements in the therapeutic efficacy in therapeutic payload delivery applications. These approaches will also enable the tailored and customized designs of MSC-based nanocarriers for personalized therapeutic applications, and finally amending the patient outcomes.
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Affiliation(s)
- Mirza Salman Baig
- Anjuman-I-Islam Kalsekar Technical Campus School of Pharmacy, Sector-16, Near Thana Naka, Khandagao, New Panvel, Navi Mumbai 410206, Maharashtra, India;
| | - Anas Ahmad
- Julia McFarlane Diabetes Research Centre (JMDRC), Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Hotchkiss Brain Institute, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, Calgary, AB T2N 4N1, Canada
| | | | - Rakesh Kumar Mishra
- School of Health Sciences and Technology, University of Petroleum and Energy Studies (UPES), Bidholi, Dehradun 248007, Uttarakhand, India;
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Li K, Huo Q, Li BY, Yokota H. Three unconventional maxims in the natural selection of cancer cells: Generation of induced tumor-suppressing cells (iTSCs). Int J Biol Sci 2023; 19:1403-1412. [PMID: 37056934 PMCID: PMC10086743 DOI: 10.7150/ijbs.79155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 02/16/2023] [Indexed: 03/14/2023] Open
Abstract
Induced tumor-suppressing cells (iTSCs) can be generated from cancer and non-cancer cells. Here, three paradoxical maxims for the action of iTSCs are reviewed: the secretion of tumor-suppressing proteins, their role as a "double-edged" sword, and the elimination of lesser-fit cancer cells. "Super-fit" cancer cells secrete an array of proteins, most of which contribute to enhancing their growth and removing "lesser-fit" cancer cells. These maxims explain the potential dilemma with therapeutic agents since the inhibitory agents tend to promote the synthesis of tumor-promoting proteins. The maxims suggest the possibility of a novel treatment option using cancer-guided evolutionary-fit iTSCs.
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Affiliation(s)
- Kexin Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Qingji Huo
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Yang S, Xiao X, Huang Z, Chen Q, Li C, Niu C, Yang Y, Yang L, Feng L. Human adipose-derived mesenchymal stem cells-based microspheres ameliorate atherosclerosis progression in vitro. Stem Cells Dev 2023. [PMID: 36762935 DOI: 10.1089/scd.2022.0287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease associated with lipids deposition which could be converted into acute clinical events by thrombosis or plaque rupture. Adipose-derived mesenchymal stem cells (ADSCs) encapsulated repair units could be an effective cure for the treatment of AS patients. Here, we encapsulate human ADSCs in collagen microspheres to fabricate stem cell repair units. Besides, we show that encapsulation in collagen microspheres and cultured in vitro for 14 days maintain the viability and stemness of human ADSCs. Moreover, we generate AS progression model and niche in vitro by combining hyperlipemia serum of AS patients with AS cell models. We further systematically demonstrate that human ADSCs-based microspheres could ameliorate AS progression by inhibiting oxidative stress injure, cell apoptosis, endothelial dysfunction, inflammation, and lipid accumulation. In addition, we perform transcriptomic analysis and functional studies to demonstrate how human ADSCs (3D cultured in microspheres) respond to AS niche compared with healthy microenvironment. These findings reveal a role for ADSCs-based microspheres in the treatment of AS and provide new ideas for stem cell therapy in cardiovascular disease. The results may have implications for improving the efficiency of human ADSC therapies by illuminating the mechanisms of human ADSCs exposed in special pathological niche.
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Affiliation(s)
- Shaojie Yang
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Xiong Xiao
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Ziwei Huang
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Qingyun Chen
- the Sixth People's Hospital of Chengdu, Department of Clinical Laboratory, China;
| | - Chenxi Li
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Chuan Niu
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Yuchu Yang
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Liping Yang
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
| | - Li Feng
- Sichuan University West China Hospital, 34753, Regenerative Medicine Research Center, Chengdu, China;
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Gao S, Zhang Y, Liang K, Bi R, Du Y. Mesenchymal Stem Cells (MSCs): A Novel Therapy for Type 2 Diabetes. Stem Cells Int 2022; 2022:8637493. [PMID: 36045953 PMCID: PMC9424025 DOI: 10.1155/2022/8637493] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/15/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.
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Affiliation(s)
- Shuang Gao
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuanyuan Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ran Bi
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
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Cell-based drug delivery systems and their in vivo fate. Adv Drug Deliv Rev 2022; 187:114394. [PMID: 35718252 DOI: 10.1016/j.addr.2022.114394] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/17/2022] [Accepted: 06/07/2022] [Indexed: 11/22/2022]
Abstract
Cell-based drug delivery systems (DDSs) have received attention recently because of their unique biological properties and self-powered functions, such as excellent biocompatibility, low immunogenicity, long circulation time, tissue-homingcharacteristics, and ability to cross biological barriers. A variety of cells, including erythrocytes, stem cells, and lymphocytes, have been explored as functional vectors for the loading and delivery of various therapeutic payloads (e.g., small-molecule and nucleic acid drugs) for subsequent disease treatment. These cell-based DDSs have their own unique in vivo fates, which are attributed to various factors, including their biological properties and functions, the loaded drugs and loading process, physiological and pathological circumstances, and the body's response to these carrier cells, which result in differences in drug delivery efficiency and therapeutic effect. In this review, we summarize the main cell-based DDSs and their biological properties and functions, applications in drug delivery and disease treatment, and in vivo fate and influencing factors. We envision that the unique biological properties, combined with continuing research, will enable development of cell-based DDSs as friendly drug vectors for the safe, effective, and even personalized treatment of diseases.
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Li M, Jiang Y, Hou Q, Zhao Y, Zhong L, Fu X. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther 2022; 13:146. [PMID: 35379361 PMCID: PMC8981790 DOI: 10.1186/s13287-022-02822-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/20/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy has been considered as a promising approach targeting a variety of intractable diseases due to remarkable multiple effect of MSCs, such as multilineage differentiation, immunomodulatory property, and pro-regenerative capacity. However, poor engraftment, low survival rate of transplanted MSC, and impaired donor-MSC potency under host age/disease result in unsatisfactory therapeutic outcomes. Enhancement strategies, including genetic manipulation, pre-activation, and modification of culture method, have been investigated to generate highly functional MSC, and approaches for MSC pre-activation are highlighted. In this review, we summarized the current approaches of MSC pre-activation and further classified, analysed the scientific principles and main characteristics of these manipulations, and described the pros and cons of individual pre-activation strategies. We also discuss the specialized tactics to solve the challenges in this promising field so that it improves MSC therapeutic functions to serve patients better.
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Affiliation(s)
- Meirong Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
| | - Yufeng Jiang
- Wound Repairing Department, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, China
| | - Qian Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Yali Zhao
- Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Lingzhi Zhong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
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11
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Vitale E, Rossin D, Perveen S, Miletto I, Lo Iacono M, Rastaldo R, Giachino C. Silica Nanoparticle Internalization Improves Chemotactic Behaviour of Human Mesenchymal Stem Cells Acting on the SDF1α/CXCR4 Axis. Biomedicines 2022; 10:biomedicines10020336. [PMID: 35203545 PMCID: PMC8961775 DOI: 10.3390/biomedicines10020336] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Human mesenchymal stem cell (hMSC)-based therapy is an emerging resource in regenerative medicine. Despite the innate ability of hMSCs to migrate to sites of injury, homing of infused hMSCs to the target tissue is inefficient. It was shown that silica nanoparticles (SiO2-NPs), previously developed to track the stem cells after transplantation, accumulated in lysosomes leading to a transient blockage of the autophagic flux. Since CXCR4 turnover is mainly regulated by autophagy, we tested the effect of SiO2-NPs on chemotactic migration of hMSCs along the SDF1α/CXCR4 axis that plays a pivotal role in directing MSC homing to sites of injury. Our results showed that SiO2-NP internalization augmented CXCR4 surface levels. We demonstrated that SiO2-NP-dependent CXCR4 increase was transient, and it reversed at the same time as lysosomal compartment normalization. Furthermore, the autophagy inhibitor Bafilomycin-A1 reproduced CXCR4 overexpression in control hMSCs confirming the direct effect of the autophagic degradation blockage on CXCR4 expression. Chemotaxis assays showed that SiO2-NPs increased hMSC migration toward SDF1α. In contrast, migration improvement was not observed in TNFα/TNFR axis, due to the proteasome-dependent TNFR regulation. Overall, our findings demonstrated that SiO2-NP internalization increases the chemotactic behaviour of hMSCs acting on the SDF1α/CXCR4 axis, unmasking a high potential to improve hMSC migration to sites of injury and therapeutic efficacy upon cell injection in vivo.
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Affiliation(s)
- Emanuela Vitale
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Daniela Rossin
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Sadia Perveen
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Ivana Miletto
- Department of Science and Technological Innovation, University of Eastern Piedmont, 15121 Alessandria, Italy;
| | - Marco Lo Iacono
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
| | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
- Correspondence:
| | - Claudia Giachino
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; (E.V.); (D.R.); (S.P.); (M.L.I.); (C.G.)
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12
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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13
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Yaghini E, Tacconi E, Pilling A, Rahman P, Broughton J, Naasani I, Keshtgar MRS, MacRobert AJ, Della Pasqua O. Population pharmacokinetic modelling of indium-based quantum dot nanoparticles: preclinical in vivo studies. Eur J Pharm Sci 2020; 157:105639. [PMID: 33188925 PMCID: PMC8214104 DOI: 10.1016/j.ejps.2020.105639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/26/2020] [Accepted: 11/05/2020] [Indexed: 12/15/2022]
Abstract
There is considerable interest in biomedical applications of quantum dot (QD) nanoparticles, in particular their use as imaging agents for diagnostic applications. In order to investigate the in vivo biodistribution and the potential toxicity of quantum dots (QDs), it is crucial to develop pharmacokinetic (PK) models as basis for prediction of QDs exposure profiles over time. Here, we investigated the in vivo biodistribution of novel indium-based QDs in mice for up to three months after intravenous administration and subsequently developed a translational population PK model to scale findings to humans. This evaluation was complemented by a comprehensive overview of the in vivo toxicology of QDs in rats. The QDs were primarily taken up by the liver and spleen and were excreted via hepatobiliary and urinary pathways. A non-linear mixed effects modelling approach was used to describe blood and organ disposition characteristics of QDs using a multi-compartment PK model. The observed blood and tissue exposure to QDs was characterised with an acceptable level of accuracy at short and long-term. Of note is the fast distribution of QDs from blood into liver and spleen in the first 24 h post-injection (half-life of 28 min) followed by a long elimination profile (half-life range: 47-90 days). This is the first study to assess the PK properties of QDs using a population pharmacokinetic approach to analyse in vivo preclinical data. No organ damage was observed following systemic administration of QDs at doses as high as 48 mg/kg at 24 h, 1 week and 5 weeks post-injection. In conjunction with the data arising from the toxicology experiments, PK parameter estimates provide insight into the potential PK properties of QDs in humans, which ultimately allow prediction of their disposition and enable optimisation of the design of first-in-human QDs studies.
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Affiliation(s)
- Elnaz Yaghini
- UCL Division of Surgery and Interventional Science, University College London, Charles Bell House, 43-45 Foley Street, London, W1W 7TS, UK.
| | - Elisa Tacconi
- Clinical Pharmacology and Therapeutics Group, University College London, School of Pharmacy, BMA House, Tavistock Square, London, WC1H 9JP, UK
| | - Andrew Pilling
- ToxPath Consultancy Ltd, Church Road, Wingfield, Diss, IP21 5RA, UK
| | - Paula Rahman
- Nanoco Technologies Ltd, 46 Grafton Street, Manchester M13 9NT, UK
| | - Joe Broughton
- Nanoco Technologies Ltd, 46 Grafton Street, Manchester M13 9NT, UK
| | - Imad Naasani
- Nanoco Technologies Ltd, 46 Grafton Street, Manchester M13 9NT, UK
| | - Mohammed R S Keshtgar
- UCL Division of Surgery and Interventional Science, University College London, Charles Bell House, 43-45 Foley Street, London, W1W 7TS, UK
| | - Alexander J MacRobert
- UCL Division of Surgery and Interventional Science, University College London, Charles Bell House, 43-45 Foley Street, London, W1W 7TS, UK
| | - Oscar Della Pasqua
- Clinical Pharmacology and Therapeutics Group, University College London, School of Pharmacy, BMA House, Tavistock Square, London, WC1H 9JP, UK
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14
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Lin H, Fan T, Sui J, Wang G, Chen J, Zhuo S, Zhang H. Recent advances in multiphoton microscopy combined with nanomaterials in the field of disease evolution and clinical applications to liver cancer. NANOSCALE 2019; 11:19619-19635. [PMID: 31599299 DOI: 10.1039/c9nr04902a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Multiphoton microscopy (MPM) is expected to become a powerful clinical tool, with its unique advantages of being label-free, high resolution, deep imaging depth, low light photobleaching and low phototoxicity. Nanomaterials, with excellent physical and chemical properties, are biocompatible and easy to prepare and functionalize. The addition of nanomaterials exactly compensates for some defects of MPM, such as the weak endogenous signal strength, limited imaging materials, insufficient imaging depth and lack of therapeutic effects. Therefore, combining MPM with nanomaterials is a promising biomedical imaging method. Here, we mainly review the principle of MPM and its application in liver cancer, especially in disease evolution and clinical applications, including monitoring tumor progression, diagnosing tumor occurrence, detecting tumor metastasis, and evaluating cancer therapy response. Then, we introduce the latest advances in the combination of MPM with nanomaterials, including the MPM imaging of gold nanoparticles (AuNPs) and carbon dots (CDs). Finally, we also propose the main challenges and future research directions of MPM technology in HCC.
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Affiliation(s)
- Hongxin Lin
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Taojian Fan
- Shenzhen Engineering Laboratory of Phosphorene and Optoelectronics and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, 518060, China.
| | - Jian Sui
- Department of Gastrointestinal surgery, Fujian Provincial Hospital, Fuzhou, 350000, China
| | - Guangxing Wang
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Jianxin Chen
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Shuangmu Zhuo
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Han Zhang
- Shenzhen Engineering Laboratory of Phosphorene and Optoelectronics and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, 518060, China.
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15
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Massive computational acceleration by using neural networks to emulate mechanism-based biological models. Nat Commun 2019; 10:4354. [PMID: 31554788 PMCID: PMC6761138 DOI: 10.1038/s41467-019-12342-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/30/2019] [Indexed: 12/11/2022] Open
Abstract
For many biological applications, exploration of the massive parametric space of a mechanism-based model can impose a prohibitive computational demand. To overcome this limitation, we present a framework to improve computational efficiency by orders of magnitude. The key concept is to train a neural network using a limited number of simulations generated by a mechanistic model. This number is small enough such that the simulations can be completed in a short time frame but large enough to enable reliable training. The trained neural network can then be used to explore a much larger parametric space. We demonstrate this notion by training neural networks to predict pattern formation and stochastic gene expression. We further demonstrate that using an ensemble of neural networks enables the self-contained evaluation of the quality of each prediction. Our work can be a platform for fast parametric space screening of biological models with user defined objectives. Mechanistic models provide valuable insights, but large-scale simulations are computationally expensive. Here, the authors show that it is possible to explore the dynamics of a mechanistic model over a large set of parameters by training an artificial neural network on a smaller set of simulations.
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16
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Jin W, Liang X, Brooks A, Futrega K, Liu X, Doran MR, Simpson MJ, Roberts MS, Wang H. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ 2018; 6:e6072. [PMID: 30564525 PMCID: PMC6286806 DOI: 10.7717/peerj.6072] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/05/2018] [Indexed: 01/12/2023] Open
Abstract
Background Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. Results Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. Discussion The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.
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Affiliation(s)
- Wang Jin
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Xiaowen Liang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Anastasia Brooks
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Kathryn Futrega
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia
| | - Xin Liu
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Michael R Doran
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia.,Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.,Australian National Centre for the Public Awareness of Science, Australian National University, Canberra, Australia
| | - Matthew J Simpson
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Michael S Roberts
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.,School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia
| | - Haolu Wang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia
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17
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Evaluation of the Biodistribution of Human Dental Pulp Stem Cells Transplanted into Mice. J Endod 2018; 44:592-598. [PMID: 29370943 DOI: 10.1016/j.joen.2017.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 11/25/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Several studies have attempted to use human dental pulp stem cells (hDPSCs) for pulp-dentin complex regeneration in vitro. However, the safety of such applications should be first evaluated in vivo before their use in clinical trials. The purpose of this study was to investigate the in vivo fate of intrapulpally transplanted hDPSCs. METHODS hDPSCs were isolated and cultured from impacted third molars. In vivo experiments were performed using 7-week-old male BALB/c nude mice. Under deep anesthesia, 1 × 105 hDPSCs were transplanted in mice via the tail vein for intravenous injection or into the pulp chamber for intrapulpal transplantation. A total of 56 mice, 28 per group, were used. Mice were sacrificed at different time points, and the numbers of hDPSCs in the organs were analyzed quantitatively. In addition, qualitative analysis was performed to detect intrapulpally transplanted hDPSCs. RESULTS Intravenously injected hDPSCs were mostly distributed to the lungs and rarely detected in other organs at all observed time points. The hDPSCs transplanted into the pulp chamber rarely migrated to other organs over time. CONCLUSIONS These data indicate a differential distribution of transplanted hDPSCs between the intravenous and intrapulpal route and show the safety of pulpal transplantation of hDPSCs.
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18
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Brooks A, Futrega K, Liang X, Hu X, Liu X, Crawford DHG, Doran MR, Roberts MS, Wang H. Concise Review: Quantitative Detection and Modeling the In Vivo Kinetics of Therapeutic Mesenchymal Stem/Stromal Cells. Stem Cells Transl Med 2017; 7:78-86. [PMID: 29210198 PMCID: PMC5746161 DOI: 10.1002/sctm.17-0209] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/02/2017] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell‐based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long‐term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine2018;7:78–86
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Affiliation(s)
- Anastasia Brooks
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Kathryn Futrega
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia
| | - Xiaowen Liang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia
| | - Xiaoling Hu
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia
| | - Xin Liu
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia
| | - Darrell H G Crawford
- School of Clinical Medicine, The University of Queensland, Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Australia
| | - Michael R Doran
- Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.,Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia.,Australian National Centre for the Public Awareness of Science, Australian National University, Canberra, Australia
| | - Michael S Roberts
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia.,School of Pharmacy and Medical Sciences, University of South Australia, Basil Hetzel Institute, Adelaide, Australia
| | - Haolu Wang
- Therapeutics Research Centre, The University of Queensland Diamantina Institute, Brisbane, Australia.,Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
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19
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Wang H, Thorling CA, Xu ZP, Crawford DHG, Liang X, Liu X, Roberts MS. Visualization and Modeling of the In Vivo Distribution of Mesenchymal Stem Cells. ACTA ACUST UNITED AC 2017; 43:2B.8.1-2B.8.17. [PMID: 29140565 DOI: 10.1002/cpsc.39] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This unit describes a protocol for elucidating the in vivo disposition of administered mesenchymal stem cells (MSCs). Specifically, direct visualization of donor cell spatiotemporal distribution and assessment of donor cell quantity in recipient organs are described. Protocols for data analysis are suggested, with the goal of developing a model to characterize and predict the physiological kinetics of administered MSCs. The use of this model is described, suggesting that it can be applied to abnormal conditions and has potential interspecies and inter-route predictive capability. These universal methods can be employed, regardless of the type of stem cell or disease, to guide future experiments and design treatment protocols. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- Haolu Wang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia.,Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Camilla A Thorling
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia
| | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia
| | - Darrell H G Crawford
- School of Medicine, The University of Queensland, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Australia
| | - Xiaowen Liang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia
| | - Xin Liu
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia
| | - Michael S Roberts
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia.,School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia
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Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 951:77-98. [PMID: 27837556 DOI: 10.1007/978-3-319-45457-3_7] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the "cryo stun effect" is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.
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21
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Dunavin N, Dias A, Li M, McGuirk J. Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease? Biomedicines 2017; 5:biomedicines5030039. [PMID: 28671556 PMCID: PMC5618297 DOI: 10.3390/biomedicines5030039] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 06/06/2017] [Accepted: 06/14/2017] [Indexed: 12/23/2022] Open
Abstract
After more than a decade of preclinical and clinical development, therapeutic infusion of mesenchymal stromal cells is now a leading investigational strategy for the treatment of acute graft-versus-host disease (GVHD). While their clinical use continues to expand, it is still unknown which of their immunomodulatory properties contributes most to their therapeutic activity. Herein we describe the proposed mechanisms, focusing on the inhibitory activity of mesenchymal stromal cells (MSCs) at immunologic checkpoints. A deeper understanding of the mechanism of action will allow us to design more effective treatment strategies.
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Affiliation(s)
- Neil Dunavin
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy., Westwood, KS 66205, USA.
| | - Ajoy Dias
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy., Westwood, KS 66205, USA.
| | - Meizhang Li
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
| | - Joseph McGuirk
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy., Westwood, KS 66205, USA.
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Wang H, Liang X, Gravot G, Thorling CA, Crawford DHG, Xu ZP, Liu X, Roberts MS. Visualizing liver anatomy, physiology and pharmacology using multiphoton microscopy. JOURNAL OF BIOPHOTONICS 2017; 10:46-60. [PMID: 27312349 DOI: 10.1002/jbio.201600083] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/18/2016] [Indexed: 05/09/2023]
Abstract
Multiphoton microscopy (MPM) has become increasingly popular and widely used in both basic and clinical liver studies over the past few years. This technology provides insights into deep live tissues with less photobleaching and phototoxicity, which helps us to better understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the healthy and diseased liver. This review summarizes the principles, opportunities, applications and limitations of MPM in hepatology. A key emphasis is on the use of fluorescence lifetime imaging (FLIM) to add additional quantification and specificity to the detection of endogenous fluorescent species in the liver as well as exogenous molecules and nanoparticles that are applied to the liver in vivo. We anticipate that in the near future MPM-FLIM will advance our understanding of the cellular and molecular mechanisms of liver diseases, and will be evaluated from bench to bedside, leading to real-time histology of human liver diseases.
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Affiliation(s)
- Haolu Wang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
| | - Xiaowen Liang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
| | - Germain Gravot
- Department of Pharmacy, University of Rennes 1, Ille-et-Vilaine, Rennes, 35043, France
| | - Camilla A Thorling
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
| | - Darrell H G Crawford
- School of Medicine, The University of Queensland, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD 4120, Australia
| | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Xin Liu
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
| | - Michael S Roberts
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia
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Dothel G, Raschi E, Rimondini R, De Ponti F. Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology. World J Gastroenterol 2016; 22:9057-9068. [PMID: 27895395 PMCID: PMC5107589 DOI: 10.3748/wjg.v22.i41.9057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/09/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn's disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves (e.g., supernatants).
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