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Xia Y, Zhang Y, Ji J, Feng G, Chen T, Li H, Zhou F, Bao Y, Zeng X, Gu Z. Urine-derived stem cells from patients alleviate lupus nephritis via regulating macrophage polarization in a CXCL14-dependent manner. Life Sci 2025; 372:123623. [PMID: 40204070 DOI: 10.1016/j.lfs.2025.123623] [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: 01/03/2025] [Revised: 03/24/2025] [Accepted: 04/03/2025] [Indexed: 04/11/2025]
Abstract
AIM Mesenchymal stem cells (MSC) exhibit hopeful therapeutic potential for the treatment of lupus nephritis (LN). Nevertheless, most MSC are harvested invasively and only transplantation of allogeneic MSC takes effect. Urine-derived stem cells (USC) can be obtained by noninvasive and safe access. Whether USC can be used for autologous stem cell transplantation to treat LN remains unknown. MATERIALS AND METHODS USC were harvested from healthy individuals, systemic lupus erythematosus (SLE) patients with no LN (NLN) and LN patients. The biological characteristics and immunomodulatory ability of three USC types were compared. Therapeutic value of USC for LN in MRL/lpr mice and influence of USC on macrophages were assessed. We further explored the mechanism of USC from LN patients (LN-USC) on macrophage polarization. KEY FINDINGS LN-USC exhibited faster proliferation and less apoptosis, significantly upregulated regulatory T cells (Treg) and downregulated antibody secreting cells (ASC). Importantly, LN-USC showed the best effect on LN in MRL/lpr mice among the three USC types. Additionally, LN-USC markedly downregulated M1 polarization of macrophages when injected into MRL/lpr mice or co-cultured with human acute monocytic leukemia cell (THP1)-derived M0 macrophages. Moreover, the regulative effect on macrophage polarization and therapeutic efficacy on LN were reversed after knocking down C-X-C motif chemokine ligand 14 (CXCL14) of LN-USC. SIGNIFICANCE These results suggested that transplantation of LN-USC alleviated LN in MRL/lpr mice via inhibiting M1 polarization of macrophages in a CXCL14-dependent manner, indicating that USC serve as a prospective candidate for autologous stem cell therapy of LN.
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Affiliation(s)
- Yunfei Xia
- Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yanju Zhang
- Infection Management Office, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Juan Ji
- Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Guijuan Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Tianxing Chen
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong 226001, China
| | - Haitao Li
- Department of Internal Medicine, Reproduction and Population Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke 9820, Belgium
| | - Fengyan Zhou
- Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yanfeng Bao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Xuhui Zeng
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong 226001, China.
| | - Zhifeng Gu
- Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
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Liu C, Liu X, Wang Y, Yu H, Li Q, Zheng Y, Fu Y, Yao G, Sun L. Mesenchymal stromal cells reduce ferroptosis of podocytes by activating the Nrf2/HO-1/GPX4 pathway in lupus nephritis. Int Immunopharmacol 2025; 153:114537. [PMID: 40147265 DOI: 10.1016/j.intimp.2025.114537] [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: 05/20/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Ferroptosis has been reported to be involved in the occurrence and development of various kidney diseases. Emerging evidence suggests that ferroptosis also plays a critical role in systemic lupus erythematosus (SLE) and lupus nephritis (LN), contributing to podocyte injury and renal dysfunction. Mesenchymal stromal cells (MSCs) have become an attractive option for podocyte injury repairing in LN. The aim of this research was to determine whether MSCs regulate ferroptosis of podocytes in LN. METHODS MSCs were injected into female MRL/lpr mice via tail vein. The symptoms of LN and the detection of ferroptosis-related biomarkers in podocytes were detected. In vitro validation was conducted by mouse podocyte cell line MPC-5. RESULTS The occurrence of ferroptosis and involvement of Nrf2/heme oxygenase-1 (HO-1) signaling pathway in podocytes were observed. We found increased expression of the podocyte marker, Wilm's tumor 1 (WT-1) and synaptopodin, following the improvement of lupus-like symptoms after MSC transplantation in MRL/lpr mice. The expression of ferroptosis-related protein glutathione peroxidase 4 (GPX4) and long chain acyl-CoA synthetase 4 (ACSL4) were elevated in renal, along with the Nrf2 and HO-1 activity enhancement. In vitro, MSC treatment maintain a stabilization of podocyte actin stress fibers, leading to an improvement of cell viability. Furthermore, our results showed that puromycin aminonucleoside (PAN) induce accumulation of cellular lipid reactive oxygen species (ROS) and glutathione depletion, and the expression of Nrf2, HO-1 and GPX4 were all downregulated whereas the expression of ACSL4 was upregulated. However, these effects were reversed by MSCs and ferroptosis inhibitor ferrastatin-1 (Fer-1). The promotion of Nrf2 nuclear translocation was observed after the treatment with MSCs. CONCLUSION Ferroptosis activation is involved in the development of LN. MSCs could ameliorate podocyte injury in LN by inhibiting ferroptosis through the Nrf2/HO-1/GPX4 pathway, which will provide novel potential therapeutic targets for LN.
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Affiliation(s)
- Chang Liu
- Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
| | - Xuanqi Liu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yujiao Wang
- Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
| | - Honghong Yu
- Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Qi Li
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Zheng
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yao Fu
- Department of Pathology, Affiliated Drum Tower Hospital, Medical School of Nanjing University.
| | - Genhong Yao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China.
| | - Lingyun Sun
- Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China.
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Wei J, Xie Z, Kuang X. Extracellular Vesicles in Renal Inflammatory Diseases: Revealing Mechanisms of Extracellular Vesicle-Mediated Macrophage Regulation. Int J Mol Sci 2025; 26:3646. [PMID: 40332144 PMCID: PMC12027779 DOI: 10.3390/ijms26083646] [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: 03/12/2025] [Revised: 04/06/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.
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Affiliation(s)
- Jiatai Wei
- The Second Clinical Medical College, Nanchang University, Nanchang 330031, China; (J.W.); (Z.X.)
| | - Zijie Xie
- The Second Clinical Medical College, Nanchang University, Nanchang 330031, China; (J.W.); (Z.X.)
| | - Xiaodong Kuang
- Pathology Teaching and Research Office, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
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Li J, Wu M, He L. Immunomodulatory effects of mesenchymal stem cell therapy in chronic kidney disease: a literature review. BMC Nephrol 2025; 26:107. [PMID: 40033224 PMCID: PMC11874639 DOI: 10.1186/s12882-025-04029-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) has been a growing public medical concern in recent years which calls for effective interventions. Mesenchymal stem cells (MSCs) have garnered increased interest in past decades due to their potential to repair and regenerate damaged tissues. Many clinical trials have highlighted the safety and effectiveness of kidney disease with this novel cell therapy. MSC infusion can improve renal function indices such as glomerular filtration rate, urine protein, serum creatinine, and blood urea nitrogen, while inhibiting immune response by increasing regulatory T cells. The therapeutic mechanisms may be primarily attributed to a function combined with immunomodulation, anti-inflammation, anti-fibrosis, promoting angiogenesis, anti-oxidation, anti-apoptosis, or tissue healing produced by cell secretsome. However, CKD is a broad concept due to many pathological etiologies including diabetes, hypertension, heart disease, immunological damage, a family history of renal failure, and so on. Furthermore, the therapeutic efficacy of MSCs may be influenced by different cell sources, injection methods, medication dosage, or homing proportion. As a result, it is timely and essential to access recent advancements in the MSC application on CKD.
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Affiliation(s)
- Jipeng Li
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Mengting Wu
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Lijie He
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China.
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Chen H, Zhang H, Zhu G, Cao L, Yu C, Duan M, Qian X, Gao X, Zhao Y. Acoustic Transmitted Decellularized Fish Bladder for Tympanic Membrane Regeneration. RESEARCH (WASHINGTON, D.C.) 2025; 8:0596. [PMID: 39916796 PMCID: PMC11794765 DOI: 10.34133/research.0596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 02/09/2025]
Abstract
Developing advanced tissue-engineered membranes with biocompatibility, suitable mechanical qualities, and anti-fibrotic and anti-inflammatory actions is important for tympanic membrane (TM) repair. Here, we present a novel acoustically transmitted decellularized fish swim bladder (DFB) loaded with mesenchymal stem cells (DFB@MSCs) for TM perforation (TMP) repair. The DFB scaffolds are obtained by removing the cellular components from the original FB, which retains the collagen composition that favors cell proliferation. Benefitting from their spatially porous structures and excellent mechanical properties, the DFB scaffolds can provide a suitable microenvironment and mechanical support for cell growth and tissue regeneration. In addition, by loading mesenchymal stem cells on the DFB scaffolds, the resultant DFB@MSCs system exhibits remarkable anti-fibrotic and anti-inflammatory effects, together with the ability to promote cell migration and angiogenesis. In vivo experiments confirm that the prepared DFB@MSCs scaffolds can not only alleviate inflammatory response caused by TMP but also promote new vessel formation, TM repair, and hearing improvement. These features indicate that our proposed DFB@MSCs stent is a prospective tool for the clinical repair of TM.
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Affiliation(s)
- Hong Chen
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
| | - Hui Zhang
- School of Life Sciences and Technology,
Southeast University, Nanjing 210096, China
| | - Guangjie Zhu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
| | - Long Cao
- Institute of Translational Medicine, Medical College,
Yangzhou University, Yangzhou 225001, Jiangsu, China
| | - Chenjie Yu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
| | - Maoli Duan
- Department of Otolaryngology Head and Neck Surgery & Audiology and Neurotology, Karolinska University Hospital,
Karolinska Institute, 171 76 Stockholm, Sweden
| | - Xiaoyun Qian
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
| | - Xia Gao
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
| | - Yuanjin Zhao
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Research Institute of Otolaryngology, Jiangsu Provincial Key Medical Discipline,
Nanjing University Medical School, Nanjing 210008, China
- School of Life Sciences and Technology,
Southeast University, Nanjing 210096, China
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Maeda K, Abdi R, Tsokos GC. The Role of Podocytes in Lupus Pathology. Curr Rheumatol Rep 2024; 27:10. [PMID: 39731699 DOI: 10.1007/s11926-024-01175-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
PURPOSE OF REVIEW Kidney injury due to lupus nephritis (LN) is a severe and sometimes life-threatening sequela of systemic lupus erythematosus. Autoimmune injury to podocytes has been increasingly demonstrated to be a key driver of LN-related kidney injury because these cells play key roles in glomerular filtration barrier homeostasis. Irreparable podocyte injury impairs these processes and can lead to proteinuria, which is an indicator of poor prognosis in LN. This review highlights recent advances in our understanding of the involvement of podocytes in the pathogenesis of LN and discusses new podocyte-targeted therapeutic strategies. RECENT FINDINGS Podocytes play a key role in glomerular filtration barrier homeostasis, both by helping to secrete and organize the glomerular basement membrane and by the formation of a glomerular slit diaphragm between adjacent cells. Recent studies revealed the involvement of abnormal calcium signaling, dysregulation of actin-related proteins, and mitotic catastrophe in LN progression. In addition, podocytes express many molecules related to the innate and adaptive immune responses. IgG from patients with LN induces direct injury of podocytes, inflammasome, and interactions with immune cells which have been shown to promote the development of LN. Our understanding of the role of podocytes in the pathogenesis of LN has been improved. Recent studies have shed light on potential therapeutic strategies targeting podocytes to control kidney injury.
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Affiliation(s)
- Kayaho Maeda
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Reza Abdi
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS-937, Boston, MA, 02215, USA.
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Cheng Y, Liu L, Ye Y, He Y, Hu W, Ke H, Guo ZY, Shao G. Roles of macrophages in lupus nephritis. Front Pharmacol 2024; 15:1477708. [PMID: 39611168 PMCID: PMC11602334 DOI: 10.3389/fphar.2024.1477708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/29/2024] [Indexed: 11/30/2024] Open
Abstract
LN is a serious complication of systemic lupus erythematosus (SLE), affecting up to 60% of patients with SLE and may lead to end-stage renal disease (ESRD). Macrophages play multifaceted roles in the pathogenesis of LN, including clearance of immune complexes, antigen presentation, regulation of inflammation, and tissue repair. Macrophages are abundant in the glomeruli and tubulointerstitium of LN patients and are positively correlated with serum creatinine levels and the severity of renal pathology. It has been shown that the infiltration of macrophages is closely associated with several clinical indicators, such as serum creatinine and complement C3 levels, anti-dsDNA antibody titers, Austin score, interstitial fibrosis and renal tubular atrophy. Moreover, cytokines expressed by macrophages were upregulated at LN onset and downregulated after remission, suggesting that macrophages may serve as markers of LN pathogenesis and remission. Therapies targeting macrophages have been shown to alleviate LN. There are two main types of macrophages in the kidney: kidney-resident macrophages (KRMs) and monocyte-derived macrophages (MDMs). KRMs and MDMs play different pathological roles in LN, with KRMs promoting leukocyte recruitment at sites of inflammation by expressing monocyte chemokines, while MDMs may exacerbate autoimmune responses by presenting immune complex antigens. Macrophages exhibit high plasticity and can differentiate into various phenotypes in response to distinct environmental stimuli. M1 (proinflammatory) macrophages are linked to the progression of active SLE, whereas the M2 (anti-inflammatory) phenotype is observed during the remission phase of LN. The polarization of macrophages in LN can be manipulated through multiple pathways, such as the modulation of signaling cascades including TLR 2/1, S1P, ERS, metabolic reprogramming, and HMGB1. This paper provides a comprehensive overview of the role of macrophages in the progression of lupus nephritis (LN), and elucidates how these cells and their secretory products function as indicators and therapeutic targets for the disease in the context of diagnosis and treatment of LN.
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Affiliation(s)
- Yaqian Cheng
- Department of Nephrology, Wenzhou Central Hospital, Wenzhou, China
| | - Lulu Liu
- Department of Nephrology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yufei Ye
- Department of Nephrology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yingxue He
- Department of Nephrology, Wenzhou Central Hospital, Wenzhou, China
| | - Wenwen Hu
- Department of Nephrology, Wenzhou Central Hospital, Wenzhou, China
| | - Haiyan Ke
- Department of Nephrology, Wenzhou Central Hospital, Wenzhou, China
| | - Zhi-Yong Guo
- Department of Nephrology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guojian Shao
- Department of Nephrology, Wenzhou Central Hospital, Wenzhou, China
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Niu Y, Jin Y, Hao Y, Liang W, Tang F, Qin Z, Liang T, Shi L. Paeonol interferes with lupus nephritis by regulating M1/M2 polarization of macrophages. Mol Immunol 2024; 169:66-77. [PMID: 38503139 DOI: 10.1016/j.molimm.2024.03.004] [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: 10/02/2023] [Revised: 02/25/2024] [Accepted: 03/11/2024] [Indexed: 03/21/2024]
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology. It is marked by the production of pathogenic autoantibodies and the deposition of immune complexes. Lupus nephritis (LN) is a prevalent and challenging clinical complications of SLE. Cortex Moutan contains paeonol as its main effective component. In this study, using the animal model of SLE induced by R848, it was found that paeonol could alleviate the lupus-like symptoms of lupus mouse model induced by R848 activating TLR7, reduce the mortality and ameliorate the renal damage of mice. In order to explore the mechanism of paeonol on lupus nephritis, we studied the effect of paeonol on the polarization of Raw264.7 macrophages in vitro. The experimental results show that paeonol can inhibit the polarization of macrophages to M1 and promote their polarization to M2, which may be related to the inhibition of MAPK and NF-κB signaling pathways. Our research provides a new insight into paeonol in the treatment of lupus nephritis, which is of great importance for the treatment of systemic lupus erythematosus and its complications.
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Affiliation(s)
- Yuzhen Niu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yingying Jin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yongxi Hao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Wei Liang
- Department of Traditional Chinese Medicine, Air Force Hospital, Eastern Theater of the Chinese People's Liberation Army, Nanjing, Jiangsu, China
| | - Fan Tang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ziyi Qin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tao Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Le Shi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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Wu D, Jiang T, Zhang S, Huang M, Zhu Y, Chen L, Zheng Y, Zhang D, Yu H, Yao G, Sun L. Blockade of Notch1 Signaling Alleviated Podocyte Injury in Lupus Nephritis Via Inhibition of NLRP3 Inflammasome Activation. Inflammation 2024; 47:649-663. [PMID: 38085465 DOI: 10.1007/s10753-023-01935-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 10/24/2023] [Accepted: 11/20/2023] [Indexed: 05/07/2024]
Abstract
To explore the role of Notch1 pathway in the pathogenesis of podocyte injury, and to provide novel strategy for podocyte repair in lupus nephritis (LN). Bioinformatics analysis and immunofluorescence assay were applied to determine the expression and localization of Notch1 intracellular domain1 (NICD1) in kidneys of LN patients and MRL/lpr mice. The stable podocyte injury model in vitro was established by puromycin aminonucleoside (PAN) treatment. Expression of inflammasome activation related gene was detected by qPCR. The podocytes with PAN treatment were cultured with or without N-S-phenyl-glycine-t-butylester (DAPT), an inhibitor of Notch1 pathway. NICD1, Wilm'stumor1 (WT1), nucleotide-binding oligomerization domain-like receptors 3 (NLRP3), and absent in melanoma-like receptors 2 (AIM2) were detected by western blot. In vivo, MRL/lpr mice were administrated with DAPT or vehicle. The LN symptoms were assessed. The podocyte injury was evaluated, and the NLRP3 in podocytes of mice was detected. Notch1 pathway was overactivated in glomeruli of LN patients. NICD1 was colocalized with podocytes of LN patients and MRL/lpr mice. The inflammasome-related genes were significantly increased in podocytes with PAN treatment. NICD1 and NLRP3 were significantly decreased, while WT1 was significantly increased in injured podocytes treated with DAPT in vitro. In vivo, lupus-like symptoms were alleviated in DAPT treatment group. Notch1 pathway was inhibited in kidneys of mice treated with DAPT. The renal inflammation was reduced and the podocyte injury was mitigated in DAPT treatment group. The NLRP3 was decreased in podocytes of mice treated with DAPT. Notch1 pathway was overactivated in podocytes of LN patients and MRL/lpr mice. Blockade of Notch1 pathway reduced renal inflammation and alleviated podocyte injury via inhibition of NLRP3 inflammasome activation in LN.
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Affiliation(s)
- Dan Wu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Tingting Jiang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Shiyi Zhang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Mengxi Huang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Ying Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Liang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Conversion therapy center for Hepatobiliary and Pancreatic Tumors, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Yuanyuan Zheng
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Dongdong Zhang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Honghong Yu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, People's Republic of China.
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Javanmardi Z, Mahmoudi M, Rafatpanah H, Rezaieyazdi Z, Shapouri-Moghaddam A, Ahmadi P, Mollazadeh S, Tabasi NS, Esmaeili SA. Tolerogenic probiotics Lactobacillus delbrueckii and Lactobacillus rhamnosus promote anti-inflammatory profile of macrophages-derived monocytes of newly diagnosed patients with systemic lupus erythematosus. Cell Biochem Funct 2024; 42:e3981. [PMID: 38509733 DOI: 10.1002/cbf.3981] [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: 12/09/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
Systemic lupus erythematosus (SLE) is known as an autoimmune disorder that is characterized by the breakdown of self-tolerance, resulting in disease onset and progression. Macrophages have been implicated as a factor in the development of SLE through faulty phagocytosis of dead cells or an imbalanced M1/M2 ratio. The study aimed to investigate the immunomodulatory effects of Lactobacillus delbrueckii and Lactobacillus rhamnosus on M1 and M2 macrophages in new case lupus patients. For this purpose, blood monocytes were collected from lupus patients and healthy people and were cultured for 5 days to produce macrophages. For 48 h, the macrophages were then cocultured with either probiotics or lipopolysaccharides (LPS). Flow cytometry and real-time polymerase chain reaction were then used to analyze the expression of cluster of differentiation (CD) 14, CD80, and human leukocyte antigen - DR (HLADR) markers, as well as cytokine expression (interleukin [IL]1-β, IL-12, tumor necrosis factor α [TNF-α], IL-10, and transforming growth factor beta [TGF-β]). The results indicated three distinct macrophage populations, M0, M1, and M2. In both control and patient-derived macrophage-derived monocytes (MDMs), the probiotic groups showed a decrease in CD14, CD80, and HLADR expression compared to the LPS group. This decrease was particularly evident in M0 and M2 macrophages from lupus patients and M1 macrophages from healthy subjects. In addition, the probiotic groups showed increased levels of IL-10 and TGF-β and decreased levels of IL-12, IL1-β, and TNF-α in MDMs from both healthy and lupus subjects compared to the LPS groups. Although there was a higher expression of pro-inflammatory cytokines in lupus patients, there was a higher expression of anti-inflammatory cytokines in healthy subjects. In general, L. delbrueckii and L. rhamnosus could induce anti-inflammatory effects on MDMs from both healthy and lupus subjects.
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Affiliation(s)
- Zahra Javanmardi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Centre, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Rezaieyazdi
- Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Parisa Ahmadi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Nafiseh Sadat Tabasi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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11
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Yu H, Li Q, Zhu H, Liu C, Chen W, Sun L. Mesenchymal stem cells attenuate systemic lupus erythematosus by inhibiting NLRP3 inflammasome activation through Pim-1 kinase. Int Immunopharmacol 2024; 126:111256. [PMID: 37992447 DOI: 10.1016/j.intimp.2023.111256] [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: 08/09/2023] [Revised: 11/08/2023] [Accepted: 11/15/2023] [Indexed: 11/24/2023]
Abstract
The inflammatory response runs through the whole pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSC) have exhibited a positive therapeutic effect on SLE. This study aimed to ascertain the pathogenic role of inflammasome activation in SLE and whether MSC alleviate SLE by suppressing it. The results showed that the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome was activated in macrophages from MRL/lpr mice and patients with SLE, correlating with disease activity. After MSC transplantation, the disease severity in MRL/lpr mice was alleviated, and NLRP3 inflammasome activation was inhibited with decreased levels of NLRP3 and caspase-1 in macrophages. Furthermore, lower serum levels of interleukin (IL)-1β and IL-18 were observed in patients with SLE who underwent MSC transplantation. In vitro and in vivo studies indicated that MSC suppressed NLRP3 inflammasome activation by inhibiting Pim-1 expression. The findings provide an updated view of inflammasome signaling in SLE. Additionally, MSC ameliorated SLE by inhibiting NLRP3 inflammasome activation, implying a possible molecular mechanism for the clinical application of MSC and a potential therapeutic target in patients with SLE.
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Affiliation(s)
- Honghong Yu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Qi Li
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huimin Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chang Liu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.
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Liang Z, Zhang G, Gan G, Liu X, Liu H, Nie D, Ma L. Mesenchymal Stromal Cells Regulate M1/M2 Macrophage Polarization in Mice with Immune Thrombocytopenia. Stem Cells Dev 2023; 32:703-714. [PMID: 37606909 DOI: 10.1089/scd.2023.0154] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023] Open
Abstract
Mesenchymal stromal cells have shown promising effects in the treatment of immune thrombocytopenia. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effects of human bone marrow mesenchymal stromal cells (hBMSCs) and analyzed their unique role in regulating the M1/M2 macrophage ratio. We established a passive immune thrombocytopenia (ITP) mouse model and showed that there was a significant M1/M2 imbalance in ITP model mice by assessing the M1/M2 ratios in the liver, spleen, and bone marrow; we observed excessive activation of M1 cells and decreased M2 cell numbers in vivo. We have shown that systemic infusion of hBMSCs effectively elevated platelet levels after disease onset. Further analysis revealed that hBMSCs treatment significantly suppressed the number of proinflammatory M1 macrophages and enhanced the number of anti-inflammatory M2 macrophages; in addition, the levels of proinflammatory factors, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased in vivo, while the levels of the anti-inflammatory factor interleukin-10 (IL-10) were increased. In conclusion, our data suggest that hBMSCs treatment can effectively increase platelet counts, and the mechanism is related to the induction of macrophage polarization toward the anti-inflammatory M2 phenotype and the decrease in proinflammatory cytokine production, which together ameliorate innate immune disorders.
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Affiliation(s)
- Ziyang Liang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Guoyang Zhang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - GuangTing Gan
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Xiaoyan Liu
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hongyun Liu
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Danian Nie
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Liping Ma
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunol 2023; 393-394:104771. [PMID: 37783061 DOI: 10.1016/j.cellimm.2023.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023]
Abstract
Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.
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Affiliation(s)
- Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Mojgan Mohammadi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Li Z, Wang R, Wang D, Zhang S, Song H, Ding S, Zhu Y, Wen X, Li H, Chen H, Liu S, Sun L. Circulating miR-320b Contributes to CD4+ T-Cell Proliferation in Systemic Lupus Erythematosus via MAP3K1. J Immunol Res 2023; 2023:6696967. [PMID: 37928434 PMCID: PMC10622187 DOI: 10.1155/2023/6696967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/27/2023] [Accepted: 09/12/2023] [Indexed: 11/07/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies and tissue inflammation. Mesenchymal stem cells (MSCs) have emerged as a promising candidate therapy for SLE owing to the immunomodulatory and regenerative properties. Circulating miRNAs are small, single-stranded noncoding RNAs in a variety of body fluids that regulate numerous immunologic and inflammatory pathways. Recent studies have revealed many differentially expressed circulating miRNAs in autoimmune diseases including SLE. However, the role of circulating miRNAs in SLE has not been extensively studied. Here, we performed small RNA sequencing analysis to compare the circulating miRNA profiles of SLE patients before and after MSC transplantation (MSCT), and identified a significant decrease of circulating miR-320b level during MSCT. Importantly, we found that the expression of circulating miR-320b and its target gene MAP3K1 was closely associated with SLE disease activity. The in vitro experiments showed that decreased MAP3K1 level in SLE peripheral blood mononuclear cells (PBMCs) was involved in CD4+ T-cell proliferation. In MRL/lpr mice, miR-320b overexpression aggravated symptoms of SLE, while miR-320b inhibition could promote disease remission. Besides, MSCs regulate miR-320b/MAP3K1 expression both in vitro and in vivo. Our results suggested that circulating miR-320b and MAP3K1 may be involved in CD4+ T-cell proliferation in SLE. This trial is registered with NCT01741857.
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Affiliation(s)
- Zutong Li
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Rou Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shujie Zhang
- MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, China
| | - Hua Song
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shuai Ding
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yantong Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xin Wen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hui Li
- Department of Rheumatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hongwei Chen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shanshan Liu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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15
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Zhang L, Chen W, Xia N, Wu D, Yu H, Zheng Y, Chen H, Fei F, Geng L, Wen X, Liu S, Wang D, Liang J, Shen W, Jin Z, Li X, Yao G, Sun L. Mesenchymal stem cells inhibit MRP-8/14 expression and neutrophil migration via TSG-6 in the treatment of lupus nephritis. Biochem Biophys Res Commun 2023; 650:87-95. [PMID: 36791546 DOI: 10.1016/j.bbrc.2023.02.005] [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: 01/24/2023] [Accepted: 02/02/2023] [Indexed: 02/05/2023]
Abstract
Abnormal infiltration and activation of neutrophils play a pathogenic role in the development of lupus nephritis (LN). Myeloid-related proteins (MRPs), MRP-8 and -14, also known as the damage-associated molecular patterns (DAMPs), are mainly secreted by activated neutrophils in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) regulate a variety of immune cells to treat LN, but it is not clear whether MSCs can regulate neutrophils and the expression of MRP-8/14 in LN. Here, we demonstrated that neutrophil infiltration and MRP-8/14 expression were increased in the kidney of MRL/lpr mice and both decreased after MSCs transplantation. Further, the results showed that tumor necrosis factor- (TNF) stimulated gene-6 (TSG-6) in MSCs is necessary for MSCs to inhibit MRP-8/14 expression in neutrophils and neutrophil migration. In addition, small-molecule immunosuppressant had no significant effect on the expression of MRP-8/14 in neutrophils. Therefore, our results suggest that MSCs inhibited MRP-8/14 expression and neutrophil migration by secreting TSG-6 in the treatment of LN.
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Affiliation(s)
- Lingli Zhang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, PR China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Nan Xia
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Dan Wu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Honghong Yu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, PR China
| | - Yuanyuan Zheng
- Department of Rheumatology and Immunology, Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, PR China
| | - Hongwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Fei Fei
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Linyu Geng
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Xin Wen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Shanshan Liu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Dandan Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Jun Liang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Wei Shen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Ziyi Jin
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Xiaojing Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, PR China; Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, PR China.
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16
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Macrophages in Lupus Nephritis: Exploring a potential new therapeutic avenue. Clin Exp Rheumatol 2022; 21:103211. [PMID: 36252930 DOI: 10.1016/j.autrev.2022.103211] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/11/2022] [Indexed: 12/14/2022]
Abstract
Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN.
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Abstract
Abstract
The pathogenesis of connective tissue diseases (CTDs), represented by systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS), and idiopathic inflammatory myopathies (IIM), includes various immune cells involved in both innate and adaptive immunity. The mesenchymal stem cells (MSCs) are unique due to their regulatory effect on immunity. This makes them a promising therapeutic approach for patients with immune-mediated disorders such as CTD. The safety and clinical efficacy of MSC treatment in CTD have been tested in a growing number of preclinical and clinical studies. Administration of MSCs has consistently shown benefits with both symptomatic and histologic improvement in CTD animal models. MSC therapies in severe and drug-resistant CTD patients have shown promise in a number of the pilot studies, cohort studies, and randomized controlled trials in SLE, RA, and SSc, but some problems still need to be resolved in the transition from the bench to the bedside. The relevant studies in pSS and IIM are still in their infancy, but have displayed encouraging outcomes. Considerable efficacy variations have been observed in terms of the route of delivery, time of MSC injection, origin of the MSCs and dosage. Furthermore, the optimization of conventional drugs combined with MSC therapies and the applications of novel cell engineering approaches requires additional research. In this review, we summarize the current evidence about the immunoregulatory mechanism of MSCs, as well as the preclinical and clinical studies of MSC-based therapy for the treatment of CTDs.
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Chen H, Wen X, Liu S, Sun T, Song H, Wang F, Xu J, Zhang Y, Zhao Y, Yu J, Sun L. Dissecting Heterogeneity Reveals a Unique BAMBI high MFGE8 high Subpopulation of Human UC-MSCs. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 10:e2202510. [PMID: 36373720 PMCID: PMC9811468 DOI: 10.1002/advs.202202510] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 10/12/2022] [Indexed: 06/16/2023]
Abstract
Mixed human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are widely applied in clinical trials to treat various diseases due to their multipotent differentiation potential and immune regulatory activities. However, the lack of a clear understanding of their heterogeneity hampers their application to precisely treat diseases. Moreover, few studies have experimentally authenticated the functions of so-called UC-MSC subpopulations classified from scRNA-seq samples. Here, this work draws a large-scale single-cell transcriptomic atlas and identified three clusters (C1, C2, and C3), representing the primed, intermediate, and stem statuses individually. The C1 and C3 clusters feature higher expression of cytokines and stemness markers, respectively. Surprisingly, further experimental assays reveal that the BAMBIhigh MFGE8high C1 subgroup has a unique phenotype, distinct transcriptomic profile, and limited adipogenic differentiation potential but compromised immunosuppressive activity in vitro and in vivo in lupus mice. Thus, this work is helpful to clarify the nature of human UC-MSCs and to choose optimal MSC types to treat specific diseases in the future.
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Affiliation(s)
- Hongwei Chen
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Xin Wen
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Shanshan Liu
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Tian Sun
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Hua Song
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Fang Wang
- Department of BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) and School of Basic Medicine Peking Union Medical College (PUMC)Beijing100005P. R. China
| | - Jiayue Xu
- Department of BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) and School of Basic Medicine Peking Union Medical College (PUMC)Beijing100005P. R. China
| | - Yueyang Zhang
- School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing211198P. R. China
| | - Yuanjin Zhao
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
| | - Jia Yu
- Department of BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) and School of Basic Medicine Peking Union Medical College (PUMC)Beijing100005P. R. China
| | - Lingyun Sun
- Department of Rheumatology and ImmunologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008P. R. China
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Shrestha KR, Lee DH, Chung W, Lee SW, Lee BY, Yoo SY. Biomimetic virus-based soft niche for ischemic diseases. Biomaterials 2022; 288:121747. [PMID: 36041939 DOI: 10.1016/j.biomaterials.2022.121747] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 07/26/2022] [Accepted: 08/15/2022] [Indexed: 11/02/2022]
Abstract
The essential therapeutic cues provided by a nanofibrous arginine-glycine-aspartic acid-engineered M13 phage were exploited as extracellular matrix (ECM)-mimicking niches, contributing to de novo soft tissue niche engineering. The interplay of biomimetic phage cues with surrounding organ tissues was identified, and cells were implanted between tissues to achieve an appropriate soft tissue niche that enables the proper functioning of the implanted stem cells at the injured site. With the polyacrylamide (PA) hydrogel mimicking the soft tissue organ stiffness ranges, it was found that biochemical and topological cues in conjunction with the ∼1-2 kPa elastic and mechanical cues of engineered phage nanofibers in soft tissues efficiently enhance the desired response of implanted stem cells. This phage cue with angiogenic and antioxidant functions overcomes the pathological environment to support implanted cells and surrounding soft tissues at the ischemic site, thereby successfully decreasing myogenic degeneration, minimizing fibrosis, and enhancing blood vessel regeneration with M2 macrophage polarization by improving the survival of the implanted endothelial progenitor cells (EPC) in an ischemic mouse model. These biomimetic phage nanofiber cues are considerably supportive of cell therapy, as they establish promising therapeutic extracellular de novo soft tissue niches for curing ischemic diseases.
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Affiliation(s)
- Kshitiz Raj Shrestha
- BIO-IT Foundry Technology Institute, Pusan National University, Busan, 46241, Republic of Korea
| | - Do Hoon Lee
- Mechanical Engineering, Korea University, Seoul, 02841, Republic of Korea
| | - Woojae Chung
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Seung-Wuk Lee
- Bioengineering, University of California, Berkeley, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, United States
| | - Byung Yang Lee
- Mechanical Engineering, Korea University, Seoul, 02841, Republic of Korea.
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan, 46241, Republic of Korea.
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Cross Talk between Mesenchymal Stem/Stromal Cells and Innate Immunocytes Concerning Lupus Disease. Stem Cell Rev Rep 2022; 18:2781-2796. [DOI: 10.1007/s12015-022-10397-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 10/16/2022]
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21
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Quaglia M, Merlotti G, Fornara L, Colombatto A, Cantaluppi V. Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis. Int J Mol Sci 2022; 23:ijms23105760. [PMID: 35628570 PMCID: PMC9142886 DOI: 10.3390/ijms23105760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/13/2022] [Accepted: 05/20/2022] [Indexed: 12/04/2022] Open
Abstract
Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.
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Jiang B, Liu C, Guo Y, Yang H, Sun T, Zhang Y, Zhou K, Guo Y, Chen H, Sun L. Precursor structure-determined fluorescence labeling for mesenchymal stem cells among four polyethylenimine-based carbon quantum dots. Colloids Surf B Biointerfaces 2022; 213:112411. [PMID: 35176604 DOI: 10.1016/j.colsurfb.2022.112411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/17/2022] [Accepted: 02/10/2022] [Indexed: 11/25/2022]
Abstract
A series of polyethylenimine (PEI)-based CQDs have been synthesized via a hydrothermal method by mixing linear PEI with linear citric acid (CA with COOH groups, PEICA), linear glucose (G with OH groups, PEIG), cyclic hyaluronic acid (HA with COOH groups, PEIHA) and cyclic boron nitride (BN with OH groups, PEIBN). PEICA had the best labeling effect (100.00 ± 0.26%) and the lowest cytotoxicity (100.89 ± 18.00%) for mesenchymal stem cells (MSCs), followed by PEIG (91.83 ± 7.60%; 92.84 ± 5.56%), PEIHA (84.34 ± 7.87%; 61.27 ± 11.34%) and PEIBN (1.33 ± 0.84%; 22.72 ± 11.47%). The labeling effect of PEIHA for MSCs is lower than that of PEIG because the surface potential of PEIHA (6.58 mV) is higher than that of PEIG (0.50 mV). For PEIBN, it is likely that the precursor (BN) is less biocompatible than CA, HA and glucose. Thus, the linear acid (CA) is more appropriate to react with PEI for synthesizing CQDs with high labeling performance for MSCs. The control experimental results show that factors (such as surface potential, aromatic component, etc.) may all contribute to MSC labeling by PEICA. This work is helpful to design CQDs with high MSC labeling efficiency.
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Affiliation(s)
- Bo Jiang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, PR China
| | - Cong Liu
- Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, PR China
| | - Ying Guo
- Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes, Ministry of Education, College of Environment, Hohai University, Nanjing 210098, PR China
| | - Hui Yang
- Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, PR China
| | - Tian Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, PR China
| | - Yueyang Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Kangxin Zhou
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, PR China
| | - Yong Guo
- Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes, Ministry of Education, College of Environment, Hohai University, Nanjing 210098, PR China.
| | - Hongwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, PR China; Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, PR China.
| | - Lingyun Sun
- Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, PR China.
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Huang C, Meng M, Li S, Liu S, Li L, Su Y, Gao H, He S, Zhao Y, Zhang M, Hou Z, Wang W, Wang X. Umbilical Cord Mesenchymal Stem Cells Ameliorate Kidney Injury in MRL/Ipr Mice Through the TGF-β1 Pathway. Front Cell Dev Biol 2022; 10:876054. [PMID: 35478960 PMCID: PMC9037034 DOI: 10.3389/fcell.2022.876054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/04/2022] [Indexed: 01/08/2023] Open
Abstract
The therapeutic effects and mechanism of umbilical cord mesenchymal stem cells (UC-MSC) on kidney injury in MRL/Ipr mice were studied. UC-MSC, methylprednisolone (MP), and their combination were used to treat MRL/Ipr mice. The therapeutic effects were evaluated by renal function assessment, and HE, PAS, and Masson staining were carried out on renal tissues and visualized by electron microscopy. Subsequently, podocyte injury was detected by the presence of podocin in renal tissues by immunofluorescence. To further explore the mechanism, serum TGF-β1 was measured, and TGF-β1, p-Smad3, and TRAF6 in the renal tissue were detected by Western blotting. In vitro, TGF-β1 was used to stimulate podocytes, and the podocyte activity and changes in synaptopodin were observed after UC-MSC treatment. Significant improvements in renal function and pathological injury were observed in the UC-MSC group compared to the lupus nephritis (LN) model group. UC-MSC and MP treatment improved podocyte injury in MRL/Ipr mice. Western blot examination showed a significant increase in TGF-β1, p-Smad3, and TRAF6 expression in renal tissues of the LN model group, while significant downregulation of those proteins was observed in the UC-MSC group. After TGF-β1 stimulation in vitro, podocyte activity decreased, and UC-MSC treatment improved podocyte activity and restored synaptopodin expression. UC-MSC therapy could improve the deterioration of renal function and the pathological changes of the renal tissues in MRL/Ipr mice. Our study suggested that UC-MSC may improve kidney injury and podocyte injury in LN mice by inhibiting the TGF-β1 pathway.
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Affiliation(s)
- Chunkai Huang
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Mingyao Meng
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Shuo Li
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Shiyuan Liu
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Lin Li
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Yanjun Su
- Thyroid Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hui Gao
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Shan He
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Yiyi Zhao
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Min Zhang
- Thyroid Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zongliu Hou
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Wenju Wang
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
| | - Xiaodan Wang
- Scientific Research Department, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, China
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24
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Li J, Luo M, Li B, Lou Y, Zhu Y, Bai X, Sun B, Lu X, Luo P. Immunomodulatory Activity of Mesenchymal Stem Cells in Lupus Nephritis: Advances and Applications. Front Immunol 2022; 13:843192. [PMID: 35359961 PMCID: PMC8960601 DOI: 10.3389/fimmu.2022.843192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 02/17/2022] [Indexed: 12/29/2022] Open
Abstract
Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.
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Affiliation(s)
- Jicui Li
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Manyu Luo
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Yan Lou
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Baichao Sun
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Xuehong Lu
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, Changchun, China
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25
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Ameliorating role of microRNA-378 carried by umbilical cord mesenchymal stem cells-released extracellular vesicles in mesangial proliferative glomerulonephritis. Cell Commun Signal 2022; 20:28. [PMID: 35264186 PMCID: PMC8905735 DOI: 10.1186/s12964-022-00835-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 01/29/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) and their released extracellular vesicles (Evs) have shown protective effects against kidney diseases. This study aims to study the functions of umbilical cord MSCs-released Evs (ucMSC-Evs) and their implicated molecules in mesangial proliferative glomerulonephritis (MsPGN). METHODS A rat model of MsPGN was induced by anti-Thy-1.1, and rat mesangial cells (rMCs) HBZY-1 were treated with PDGF-BB/DD to mimic MsPGN condition in vitro. Rats and cells were treated with different doses of ucMSC-Evs, and then the pathological changes in renal tissues and proliferation of rMCs were determined. Differentially expressed microRNAs (miRNAs) after Evs treatment were screened by microarray analysis. The interactions among miR-378, PSMD14, and TGFBR1 were analyzed. Gain- and loss-of function studies of miR-378 and PSMD14 were performed to explore their effects on tissue hyperplasia and rMC proliferation and their interactions with the TGF-β1/Smad2/3 signaling pathway. RESULTS The ucMSC-Evs treatment ameliorated mesangial hyperplasia and fibrosis in rat renal tissues and suppressed the aberrant proliferation of rMCs in a dose-dependent manner. miR-378 was the most upregulated miRNA in tissues and cells after ucMSC-Evs treatment. miR-378 directly targeted PSMD14, and PSMD14 maintained the stability of TGFBR1 through deubiquitination modification, which led to TGF-β1/Smad2/3 activation. Either miR-378 knockdown or PSMD14 overexpression diminished the protective functions of ucMSC-Evs by activating the TGF-β1/Smad2/3 signaling pathway. CONCLUSION UcMSC-Evs ameliorate pathological process in MsPGN through the delivery of miR-378, which suppresses PSMD14-mediated TGFBR1 stability and inactivates the TGF-β1/Smad2/3 signaling pathway to reduce tissue hyperplasia and rMC proliferation. Video abstract.
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26
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Li A, Guo F, Pan Q, Chen S, Chen J, Liu HF, Pan Q. Mesenchymal Stem Cell Therapy: Hope for Patients With Systemic Lupus Erythematosus. Front Immunol 2021; 12:728190. [PMID: 34659214 PMCID: PMC8516390 DOI: 10.3389/fimmu.2021.728190] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Although previous studies have demonstrated that SLE is related to the imbalance of cells in the immune system, including B cells, T cells, and dendritic cells, etc., the mechanisms underlying SLE pathogenesis remain unclear. Therefore, effective and low side-effect therapies for SLE are lacking. Recently, mesenchymal stem cell (MSC) therapy for autoimmune diseases, particularly SLE, has gained increasing attention. This therapy can improve the signs and symptoms of refractory SLE by promoting the proliferation of Th2 and Treg cells and inhibiting the activity of Th1, Th17, and B cells, etc. However, MSC therapy is also reported ineffective in some patients with SLE, which may be related to MSC- or patient-derived factors. Therefore, the therapeutic effects of MSCs should be further confirmed. This review summarizes the status of MSC therapy in refractory SLE treatment and potential reasons for the ineffectiveness of MSC therapy from three perspectives. We propose various MSC modification methods that may be beneficial in enhancing the immunosuppression of MSCs in SLE. However, their safety and protective effects in patients with SLE still need to be confirmed by further experimental and clinical evidence.
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Affiliation(s)
- Aifen Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengbiao Guo
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Quanren Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuxian Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaxuan Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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27
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Sant'Ana AN, Araújo AB, Gonçalves FDC, Paz AH. Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages. World J Stem Cells 2021; 13:1160-1176. [PMID: 34630856 PMCID: PMC8474715 DOI: 10.4252/wjsc.v13.i9.1160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cells that have great potential as cell therapy for autoimmune and inflammatory disorders, as well as for other clinical conditions, due to their immunoregulatory and regenerative properties. MSCs modulate the inflammatory milieu by releasing soluble factors and acting through cell-to-cell mechanisms. MSCs switch the classical inflammatory status of monocytes and macrophages towards a non-classical and anti-inflammatory phenotype. This is characterized by an increased secretion of anti-inflammatory cytokines, a decreased release of pro-inflammatory cytokines, and changes in the expression of cell membrane molecules and in metabolic pathways. The MSC modulation of monocyte and macrophage phenotypes seems to be critical for therapy effectiveness in several disease models, since when these cells are depleted, no immunoregulatory effects are observed. Here, we review the effects of living MSCs (metabolically active cells) and metabolically inactive MSCs (dead cells that lost metabolic activity by induced inactivation) and their derivatives (extracellular vesicles, soluble factors, extracts, and microparticles) on the profile of macrophages and monocytes and the implications for immunoregulatory and reparative processes. This review includes mechanisms of action exhibited in these different therapeutic approaches, which induce the anti-inflammatory properties of monocytes and macrophages. Finally, we overview several possibilities of therapeutic applications of these cells and their derivatives, with results regarding monocytes and macrophages in animal model studies and some clinical trials.
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Affiliation(s)
- Alexia Nedel Sant'Ana
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
| | - Anelise Bergmann Araújo
- Centro de Processamento Celular, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil.
| | | | - Ana Helena Paz
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
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28
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Ahani-Nahayati M, Niazi V, Moradi A, Pourjabbar B, Roozafzoon R, Baradaran-Rafii A, Keshel SH. Umbilical cord mesenchymal stem/stromal cells potential to treat organ disorders; an emerging strategy. Curr Stem Cell Res Ther 2021; 17:126-146. [PMID: 34493190 DOI: 10.2174/1574888x16666210907164046] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 11/22/2022]
Abstract
Currently, mesenchymal stem/stromal cells (MSCs) have attracted growing attention in the context of cell-based therapy in regenerative medicine. Following the first successful procurement of human MSCs from bone marrow (BM), these cells isolation has been conducted from various origins, in particular, the umbilical cord (UC). Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) can be acquired by a non-invasive plan and simply cultured, and thereby signifies their superiority over MSCs derived from other sources for medical purposes. Due to their unique attributes, including self-renewal, multipotency, and accessibility concomitant with their immunosuppressive competence and lower ethical concerns, UC-MSCs therapy is described as encouraging therapeutic options in cell-based therapies. Regardless of their unique aptitude to adjust inflammatory response during tissue recovery and delivering solid milieu for tissue restoration, UC-MSCs can be differentiated into a diverse spectrum of adult cells (e.g., osteoblast, chondrocyte, type II alveolar, hepatocyte, and cardiomyocyte). Interestingly, they demonstrate a prolonged survival and longer telomeres compared with MSCs derived from other sources, suggesting that UC-MSCs are desired source to use in regenerative medicine. In the present review, we deliver a brief review of UC-MSCs isolation, expansion concomitantly with immunosuppressive activities, and try to collect and discuss recent pre-clinical and clinical researches based on the use of UC-MSCs in regenerative medicine, focusing on with special focus on in vivo researches.
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Affiliation(s)
- Milad Ahani-Nahayati
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Alireza Moradi
- Department of Physiology, School of Medicine, Iran University of Medical Science, Tehran. Iran
| | - Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | - Reza Roozafzoon
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
| | | | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran. Iran
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Yang C, Wu M, You M, Chen Y, Luo M, Chen Q. The therapeutic applications of mesenchymal stromal cells from human perinatal tissues in autoimmune diseases. Stem Cell Res Ther 2021; 12:103. [PMID: 33541422 PMCID: PMC7859900 DOI: 10.1186/s13287-021-02158-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/11/2021] [Indexed: 02/07/2023] Open
Abstract
The autoimmune diseases are characterized by overactivation of immune cells, chronic inflammation, and immune response to self-antigens, leading to the damage and dysfunction of multiple organs. Patients still do not receive desired clinical outcomes while suffer from various adverse effects imparted by current therapies. The therapeutic strategies based on mesenchymal stromal cell (MSC) transplantation have become the promising approach for the treatment of autoimmune diseases due to the immunomodulation property of MSCs. MSCs derived from perinatal tissues are collectively known as perinatal MSCs (PMSCs), which can be obtained via painless procedures from donors with lower risk of being contaminated by viruses than those MSCs from adult tissue sources. Therefore, PMSCs may be the ideal cell source for the treatment of autoimmune diseases. This article summarizes recent progress and possible mechanisms of PMSCs in treating autoimmune diseases in animal experiments and clinical studies. This review also presents existing challenges and proposes solutions, which may provide new hints on PMSC transplantation as a therapeutic strategy for the treatment of autoimmune diseases.
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Affiliation(s)
- Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China.
| | - Mingjun Wu
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China
| | - Min You
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China
| | - Yu Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China
| | - Maowen Luo
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., 15 Jinquan Road, Chengdu, 610036, China.
- Center for Stem Cell Research & Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China.
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30
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Zhao WM, Tao SM, Liu GL. Neutrophil-to-lymphocyte ratio in relation to the risk of all-cause mortality and cardiovascular events in patients with chronic kidney disease: a systematic review and meta-analysis. Ren Fail 2020; 42:1059-1066. [PMID: 33081569 PMCID: PMC7668415 DOI: 10.1080/0886022x.2020.1832521] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim To systematically evaluate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and the risk of all-cause mortality or cardiovascular events in patients with chronic kidney disease (CKD). Methods PubMed, Embase, and Web of Science databases were searched for cohort studies that were published since the databases were launched, until 1 April 2020. We selected papers according to specific inclusion and exclusion criteria, extracted data, and evaluated the quality of the citations. Data from eligible studies were used to calculate the combined hazard ratios (HRs) and 95% confidence intervals (CI). Results The search identified 1048 potentially eligible records, and 10 studies (n = 1442) were selected. Eight studies reported all-cause mortality, and two studies reported cardiovascular events. The combined HR of all-cause mortality was 1.45 (95% CI 1.20–1.75) and the HR of cardiovascular events was 1.52 (95% CI 1.33–1.72) when NLR was considered as a categorical variable. Similarly, the association between NLR and all-cause mortality was confirmed (HR 1.35; 95% CI 1.23–1.48) when NLR was used as a continuous variable. Conclusion NLR is a predictor of all-cause mortality and cardiovascular events in patients with chronic kidney disease.
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Affiliation(s)
- Wen-Man Zhao
- Department of Nephrology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Shu-Man Tao
- Department of Nephrology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Gui-Ling Liu
- Department of Nephrology, The Second Hospital of Anhui Medical University, Hefei, China
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Wang Y, Han B, Wang Y, Wang C, Zhang H, Xue J, Wang X, Niu T, Niu Z, Chen Y. Mesenchymal stem cell-secreted extracellular vesicles carrying TGF-β1 up-regulate miR-132 and promote mouse M2 macrophage polarization. J Cell Mol Med 2020; 24:12750-12764. [PMID: 32965772 PMCID: PMC7686990 DOI: 10.1111/jcmm.15860] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022] Open
Abstract
The effects of mesenchymal stem cells (MSCs) on different types of diseases are controversial, and the inner mechanisms remain unknown, which retards the utilization of MSCs in disease therapy. In this study, we aimed to elucidate the mechanisms of MSCs-extracellular vesicles (EVs) carrying transforming growth factor-beta 1 (TGF-β1) in M2 polarization in mouse macrophages via the microRNA-132 (miR-132)/E3 ubiquitin ligase myc binding protein 2 (Mycbp2)/tuberous sclerosis complex 2 (TSC2) axis. Mouse MSCs were isolated for adipogenic and osteogenic induction, followed by co-culture with mouse macrophages RAW264.7. Besides, mouse macrophages RAW264.7 were co-cultured with MSCs-EVs in vitro, where the proportion of macrophages and inflammation were detected by flow cytometry and ELISA. The experimental data revealed that MSCs-EVs promoted M2 polarization of macrophages, and elevated interleukin (IL)-10 expression and inhibited levels of IL-1β, tumour necrosis factor (TNF)-α and IL-6. MSC-EV-treated macrophages RAW264.7 increased TGF-β1 expression, thus elevating miR-132 expression. MiR-132 directly bound to Mycbp2, as confirmed by luciferase activity assay. Meanwhile, E3 ubiquitin ligase Mycbp2 could ubiquitinate TSC2 protein. Furthermore, silencing TGF-β1 inhibited M2 polarization of MSC-EV-treated macrophages. Taken conjointly, this study provides evidence reporting that MSC-secreted EVs carry TGF-β1 to promote M2 polarization of macrophages via modulation of the miR-132/Mycbp2/TSC2 axis.
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Affiliation(s)
- Yongqi Wang
- Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou, China
| | - Biao Han
- Department of Thoracic Surgery, the First Hospital of Lanzhou University, Lanzhou, China
| | - Yingbin Wang
- Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou, China
| | - Chunai Wang
- Department of Anesthesiology, Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Hong Zhang
- Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou, China
| | - Jianjun Xue
- Department of Anesthesiology, Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Xiaoqing Wang
- Department of Anesthesiology, the First Hospital of Lanzhou University, Lanzhou, China
| | - Tingting Niu
- The First School of Clinical Medicine, the First Hospital of Lanzhou University, Lanzhou, China
| | - Zhen Niu
- The First School of Clinical Medicine, the First Hospital of Lanzhou University, Lanzhou, China
| | - Yuhe Chen
- The First School of Clinical Medicine, the First Hospital of Lanzhou University, Lanzhou, China
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Song Y, Zhang TJ, Li Y, Gao Y. Mesenchymal Stem Cells Decrease M1/M2 Ratio and Alleviate Inflammation to Improve Limb Ischemia in Mice. Med Sci Monit 2020; 26:e923287. [PMID: 32860388 PMCID: PMC7477932 DOI: 10.12659/msm.923287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Limb ischemia (LI) is the underlying pathology of peripheral artery disease (PAD). Macrophages play a critical role in inflammation and can contribute to the exacerbation or reduction of inflammation. Transplantation of mesenchymal stem cells (MSCs) is an emerging therapeutic strategy for PAD. However, the mechanism by which human placenta-derived mesenchymal stem cells (PMSCs) regulate macrophage differentiation in ischemic tissue remains unclear. MATERIAL AND METHODS Placentas were obtained from healthy donors with normal 38- to 40-week gestation, and PMSCs were isolated from the placentas and cultured. A mouse model of hind-limb ischemia was established. Ischemic limbs were injected intramuscularly with about 5×10⁶ PMSCs in the PMSCs group or a placebo solution (phosphate-buffered saline) in the control group at 4 different sites 1 day after the procedure. The blood perfusion of hind-limbs and the histological morphology were observed at day 1, 7, and 14 after the surgical procedure. Macrophages were detected by flow cytometry. The expression of serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). The expression of CD31 and smooth muscle alpha-actin (alpha-SMA) in frozen muscle samples were detected by immunofluorescence staining. RESULTS In the PMSCs group, blood perfusion was gradually recovered and ischemic injury was markedly alleviated. The percentage of M2-like macrophages was increased dramatically, while the M1/M2 macrophage ratio was reduced. The expression of TNF-alpha and IL-6 was reduced, while the IL-10 level was elevated. The expression and density of CD31- and alpha-SMA-positive vessels were both significantly increased. CONCLUSIONS Transplanted PMSCs alleviated inflammation, promoted neovascularization, and improved hind limb ischemia through regulating macrophage differentiation toward the M2 phenotype and cytokine secretion. Cytokine manipulation of macrophage phenotypes may have potential therapeutic benefits in injured ischemic limbs.
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Affiliation(s)
- Ye Song
- Department of Ultrasound Medicine, The Affiliated Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China (mainland)
| | - Tian-Jie Zhang
- Shanghai Leren Dongsheng Clinic, Shanghai, China (mainland)
| | - Yuan Li
- Department of Ultrasound Medicine, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China (mainland)
| | - Yuan Gao
- Department of General Surgery, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China (mainland)
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Liao H, Li Y, Zhang X, Zhao X, Zheng D, Shen D, Li R. Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation. J Immunol Res 2020; 2020:8263598. [PMID: 32908940 PMCID: PMC7474395 DOI: 10.1155/2020/8263598] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/25/2020] [Accepted: 07/11/2020] [Indexed: 12/19/2022] Open
Abstract
Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1β levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p < 0.05). Tha 200 μg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p < 0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1β levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p < 0.05). The (Tha 200 μg/ml) MS group exhibited a decrease in TNF-α and IL-1β level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p < 0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1β levels via its modulation on M1/M2 differentiation.
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Affiliation(s)
- Hui Liao
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Yuanping Li
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Xilan Zhang
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Xiaoyun Zhao
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Dan Zheng
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Dayue Shen
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
| | - Rongshan Li
- Department of Pharmacy, Shanxi Provincial People's Hospital of Shanxi Medical University, Taiyuan 030012, China
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Nie M, Chen G, Zhao C, Gan J, Alip M, Zhao Y, Sun L. Bio-inspired adhesive porous particles with human MSCs encapsulation for systemic lupus erythematosus treatment. Bioact Mater 2020; 6:84-90. [PMID: 32817916 PMCID: PMC7419256 DOI: 10.1016/j.bioactmat.2020.07.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/26/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) therapy is a promising treatment for Systemic lupus erythematosus (SLE) patients. However, this method is encumbered by suboptimal phenotype of MSCs used in clinical settings, and a short in vivo persistence time. Herein, inspired by the natural microstructure of the sand tower worm nest, we proposed novel adhesive porous particles with human MSCs encapsulation via microfluidic electrospray technology for SLE treatment. The porous microparticles were formed by immediate gelation reaction between sodium alginate (ALG) and poly-d-lysine (PDL), and then sacrificed polyethylene oxide (PEO) to form the pores. The resultant microparticles could protect MSCs from immune cells while maintain their immune modulating functions, and achieve rapid exchange of nutrients from the body. In addition, owing to the electrostatic adsorption and covalent bonding between PDL and tissues, the porous microparticles could adhere to the bowel surfaces tightly after intraperitoneal injection. Through in vivo imaging system (IVIS) methods and in vivo study, it was demonstrated that the MSCs-encapsulated porous adhesive microparticles could significantly increase the cellular half-life, turn activated inflammatory macrophages into an anti-inflammatory profile, and ameliorate disease progression in MRL/lpr mice. Thus, the MSCs-encapsulated porous microparticles showed distinctive functions in chronic SLE treatment, with additional potential to be used in a variety of biomedical applications.
We proposed novel adhesive porous particles with MSCs encapsulation. MSCs could turn activated inflammatory macrophages into an anti-inflammatory profile. The porous microparticles could adhere to bowel surfaces tightly through electrostatic adsorption and covalent bonding. MSCs-encapsulated porous adhesive microparticles could significantly ameliorate disease progression in MRL/lpr mice.
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Affiliation(s)
- Min Nie
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
| | - Guopu Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
| | - Cheng Zhao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
| | - Jingjing Gan
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
| | - Mihribangvl Alip
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
| | - Yuanjin Zhao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China.,State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210002, China
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Qi J, Tang X, Li W, Chen W, Yao G, Sun L. Mesenchymal stem cells inhibited the differentiation of MDSCs via COX2/PGE2 in experimental sialadenitis. Stem Cell Res Ther 2020; 11:325. [PMID: 32727564 PMCID: PMC7391592 DOI: 10.1186/s13287-020-01837-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/25/2020] [Accepted: 07/16/2020] [Indexed: 12/15/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) can regulate innate and adaptive immune systems through interacting with immune cells directly and secreting multiple soluble factors. Due to their immunosuppressive properties, MSC transplantation has been applied to treat many clinical and experimental autoimmune diseases. However, the therapeutic effects and mechanisms by which MSCs regulate myeloid cells in Sjögren’s syndrome (SS) still remain elusive. Methods The number and immune-suppressive activity of myeloid-derived suppressor cells (MDSCs), polymorphonuclear MDSCs (PMN-MDSCs), and monocytic MDSCs (M-MDSCs) were determined in non-obese diabetic (NOD) mice with sialadenitis and in NOD mice with human umbilical cord-derived MSC (UC-MSC) transplantation. Bone marrow cells were cultured with MSC-conditioned medium (MSC-CM) for 4 days. The number and immune-suppressive gene of MDSCs were detected by flow cytometry or qRT-PCR. Results The results showed that the number of MDSCs and PMN-MDSCs was higher and M-MDSCs were lower in NOD mice with sialadenitis. UC-MSCs ameliorated SS-like syndrome by reducing MDSCs, PMN-MDSCs, and M-MDSCs and promoting the suppressive ability of MDSCs significantly in NOD mice. UC-MSCs inhibited the differentiation of MDSCs. In addition, UC-MSCs enhanced the suppressive ability of MDSCs in vitro. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2 (PGE2) and inhibited the differentiation of M-MDSCs through secreting interferon-β (IFN-β). Conclusions Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in NOD mice with sialadenitis.
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Affiliation(s)
- Jingjing Qi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.,Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, People's Republic of China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China
| | - Wenchao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210093, People's Republic of China.
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Chen W, Li W, Zhang Z, Tang X, Wu S, Yao G, Li K, Wang D, Xu Y, Feng R, Duan X, Fan X, Lu L, Chen W, Li C, Sun L. Lipocalin-2 Exacerbates Lupus Nephritis by Promoting Th1 Cell Differentiation. J Am Soc Nephrol 2020; 31:2263-2277. [PMID: 32646856 DOI: 10.1681/asn.2019090937] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 05/24/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. METHODS The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lpr mice and analyzing pristane-treated LCN2 -/- mice. RESULTS LCN2 is highly expressed in CD4+ T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-γ overexpression in CD4+ T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. CONCLUSIONS LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.
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Affiliation(s)
- Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Wenchao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Zhuoya Zhang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Shufang Wu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Kang Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Dandan Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Yuemei Xu
- Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Ruihai Feng
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Xiaoxiao Duan
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
| | - Xiangshan Fan
- Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Liwei Lu
- Department of Pathology, Center of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Chaojun Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China .,State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China .,State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China
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Mesenchymal Stem Cells Enhance Pulmonary Antimicrobial Immunity and Prevent Following Bacterial Infection. Stem Cells Int 2020; 2020:3169469. [PMID: 32300367 PMCID: PMC7142356 DOI: 10.1155/2020/3169469] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 12/21/2022] Open
Abstract
Background Immunosuppressants such as cyclophosphamide (CTX) have been employed to treat a wide array of autoimmune diseases. The most unfavourable side effects of these drugs are their suppression on the antimicrobial immunity and increasing the risk of infection. As a promising substitution/adjunct, mesenchymal stem cells (MSCs) are currently being tested in several clinical trials. However, their influence on the recipients' antimicrobial immunity remains unclear. Methods In this study, C57BL/6 mice were treated with either CTX or MSCs, and then both the innate and adaptive immunity of the lung were determined. To investigate the influence of CTX and MSCs on the immune defence against infection, the treated mice were intranasally infected with opportunistic pathogen Haemophilus influenzae (Hi). Bacterial clearance and antibacterial immune responses were analysed. Results Our data showed that CTX strongly inhibited the proliferation of lung immune cells, including alveolar macrophages (AMs) and T cells, whereas MSCs increased the numbers of these cells. CTX suppressed the phagocytic activity of AMs; on the contrary, MSCs enhanced it. Notably, infusion of MSCs led to a remarkable increase of regulatory T cells and Th1 cells in the lung. When infected by Hi, CTX did not significantly impair the elimination of invaded bacteria. However, MSC-treated mice exhibited accelerated bacterial clearance and moderate inflammation and tissue damage. Conclusion Our study reported that unlike traditional immunosuppressants, modulation of MSCs on the recipient's immune response is more elegant. It could preserve and even enhance the antimicrobial defence, suggesting that MSCs are better choice for patients with high risk of infection or those who need long-term immunosuppressive regimen.
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Anders HJ. 2019 Update in basic kidney research: microbiota in chronic kidney disease, controlling autoimmunity, kidney inflammation and modelling the glomerular filtration barrier. Nephrol Dial Transplant 2020; 35:4-9. [PMID: 31943087 DOI: 10.1093/ndt/gfz219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 09/30/2019] [Indexed: 12/25/2022] Open
Affiliation(s)
- Hans-Joachim Anders
- Renal Division, Department of Medicine IV, University Hospital, LMU Munich, München, Germany
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Zhou T, Liao C, Li HY, Lin W, Lin S, Zhong H. Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis. Stem Cell Res Ther 2020; 11:48. [PMID: 32019582 PMCID: PMC7001209 DOI: 10.1186/s13287-019-1538-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/11/2019] [Accepted: 12/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Lupus nephritis is usually manifested by proteinuria, active urinary sediment, hypertension, and renal failure and is a serious complication with more than 50% occurrence in systemic lupus erythematosus patients. Mesenchymal stem cells (MSC) present remarkable immunomodulatory ability, and these cells are potential therapeutic agents for autoimmune disorders. In clinical trials, the effectiveness of MSC in the treatment of lupus nephritis is still controversial. A meta-analysis was performed to assess whether MSC can achieve good efficacy in the treatment of lupus nephritis in mice. METHODS A comprehensive literature search was performed in Cochrane Library, ISI Web of Science, PubMed, and EMBASE from inception to Oct 1, 2019. Two authors independently extracted the data, which were pooled and calculated using RevMan 5.3. RESULTS A total of 28 studies met the inclusion criteria. MSC treatment resulted in lower levels of ds-DNA (OR = - 29.58, 95% CI - 29.58, - 17.99; P < 0.00001), ANA (OR = - 70.93, 95% CI - 104.55, - 37.32; P < 0.0001), Scr (OR = - 8.20, 95% CI - 12.71, - 3.69; P = 0.0004), BUN (OR = - 14.57, 95% CI - 20.50, - 8.64; P < 0.00001), proteinuria (OR = - 4.26, 95% CI - 5.15 to - 3.37; P < 0.00001), and renal sclerosis score (OR = - 1.92, 95% CI - 2.66 to - 1.18; P < 0.00001), and MSC treatment could get higher levels of albumin. To detect the potential, the cytokines were also assessed, and the MSC treatment group had lower levels of IL-2, IL-12, IL-17, and IFN-γ when compared with the control group. However, the difference was not notable for IL-4, IL-6, IL-10, TGF-β, MCP-1, TNF-α, Th1, Th17, Foxp3, or Tregs. CONCLUSION Our study confirmed that MSC treatment in an animal model for lupus nephritis in the studies included in the meta-analysis resulted in lower levels of ds-DNA, ANA, Scr, BUN, proteinuria, and renal sclerosis score, and MSC treatment could get higher levels of albumin.
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Affiliation(s)
- Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, 515041, No. 69 Dongsha Road, Shantou, China.
| | - Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, 515041, No. 69 Dongsha Road, Shantou, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, 510800, China
| | - Wenshan Lin
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, 515041, No. 69 Dongsha Road, Shantou, China
| | - Shujun Lin
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, 515041, No. 69 Dongsha Road, Shantou, China
| | - Hongzhen Zhong
- Department of Nephrology, the Second Affiliated Hospital, Shantou University Medical College, 515041, No. 69 Dongsha Road, Shantou, China
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Lu X, Li N, Zhao L, Guo D, Yi H, Yang L, Liu X, Sun D, Nian H, Wei R. Human umbilical cord mesenchymal stem cells alleviate ongoing autoimmune dacryoadenitis in rabbits via polarizing macrophages into an anti-inflammatory phenotype. Exp Eye Res 2019; 191:107905. [PMID: 31891674 DOI: 10.1016/j.exer.2019.107905] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/08/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) exhibit beneficial effects on autoimmune dacryoadenitis. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on rabbit autoimmune dacryoadenitis, an animal model of Sjögren's syndrome (SS) dry eye, and explored whether the effects of MSCs were related to their modulation on macrophage polarization. We have showed that systemic infusion of hUC-MSCs after disease onset efficiently diminished the chronic inflammation in diseased LGs and improved the clinical symptoms. Further analysis revealed that hUC-MSC treatment significantly inhibited the expression of pro-inflammatory M1 macrophage markers iNOS, TNF-α and IL-6, and promoted the expression of anti-inflammatory M2 macrophage markers Arg1, CD206, IL-10, IL-4 and TGF-β in LGs. Mechanistically, hUC-MSCs activated AKT pathway in macrophages, resulting in upregulation of M2-associated molecule Arg1, which was partly abolished by PI3K inhibitor, LY294002. Together, our data indicated that hUC-MSCs can skew macrophages into an M2 phenotype via affecting AKT pathway. These data may provide a new insight into the mechanisms of hUC-MSCs in the therapy of SS dry eye.
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Affiliation(s)
- Xiaoxiao Lu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Na Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Lu Zhao
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Di Guo
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Huanfa Yi
- Central Laboratory of the Eastern Division, The First Hospital, Jilin University, Changchun, China
| | - Liyuan Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Xun Liu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Deming Sun
- Doheny Eye Institute, And Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA
| | - Hong Nian
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
| | - Ruihua Wei
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
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