|
1
|
Cen K, Huang Y, Xie Y, Liu Y. The guardian of intracranial vessels: Why the pericyte? Biomed Pharmacother 2024; 176:116870. [PMID: 38850658 DOI: 10.1016/j.biopha.2024.116870] [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: 03/02/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024] Open
Abstract
Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused by plaque formation. This condition leads to reduced blood flow to the brain, resulting in cerebral ischemia and hypoxia. Ischemic stroke (IS) resulting from ICAS poses a significant global public health challenge, especially among East Asian populations. However, the underlying causes of the notable variations in prevalence among diverse populations, as well as the most effective strategies for preventing and treating the rupture and blockage of intracranial plaques, remain incompletely comprehended. Rupture of plaques, bleeding, and thrombosis serve as precipitating factors in the pathogenesis of luminal obstruction in intracranial arteries. Pericytes play a crucial role in the structure and function of blood vessels and face significant challenges in regulating the Vasa Vasorum (VV)and preventing intraplaque hemorrhage (IPH). This review aims to explore innovative therapeutic strategies that target the pathophysiological mechanisms of vulnerable plaques by modulating pericyte biological function. It also discusses the potential applications of pericytes in central nervous system (CNS) diseases and their prospects as a therapeutic intervention in the field of biological tissue engineering regeneration.
Collapse
Affiliation(s)
- Kuan Cen
- Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China
| | - YinFei Huang
- Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China
| | - Yu Xie
- Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China
| | - YuMin Liu
- Department of Neurology, Zhongnan Hospital Affiliated to Wuhan University, Wuhan 430000, China.
| |
Collapse
|
|
2
|
Zhang Q, Yan X, Han H, Wang Y, Sun J. Pericyte in retinal vascular diseases: A multifunctional regulator and potential therapeutic target. FASEB J 2024; 38:e23679. [PMID: 38780117 DOI: 10.1096/fj.202302624r] [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: 12/19/2023] [Revised: 04/17/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024]
Abstract
Retinal vascular diseases (RVDs), in particular diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, are leading contributors to blindness. The pathogenesis of RVD involves vessel dilatation, leakage, and occlusion; however, the specific underlying mechanisms remain unclear. Recent findings have indicated that pericytes (PCs), as critical members of the vascular mural cells, significantly contribute to the progression of RVDs, including detachment from microvessels, alteration of contractile and secretory properties, and excessive production of the extracellular matrix. Moreover, PCs are believed to have mesenchymal stem properties and, therefore, might contribute to regenerative therapy. Here, we review novel ideas concerning PC characteristics and functions in RVDs and discuss potential therapeutic strategies based on PCs, including the targeting of pathological signals and cell-based regenerative treatments.
Collapse
Affiliation(s)
- Quan Zhang
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Air Force Medical University, Xi'an, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an, China
| | - Xianchun Yan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an, China
| | - Hua Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an, China
| | - Yusheng Wang
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Jiaxing Sun
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Air Force Medical University, Xi'an, China
- Department of Neurobiology, Air Force Medical University, Xi'an, China
| |
Collapse
|
|
3
|
Cosentino A, Agafonova A, Modafferi S, Trovato Salinaro A, Scuto M, Maiolino L, Fritsch T, Calabrese EJ, Lupo G, Anfuso CD, Calabrese V. Blood-Labyrinth Barrier in Health and Diseases: Effect of Hormetic Nutrients. Antioxid Redox Signal 2024; 40:542-563. [PMID: 37565276 DOI: 10.1089/ars.2023.0251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Significance: The stria vascularis, located in the inner ear, consists of three layers, one of which is the blood-labyrinth barrier (BLB). It is formed by endothelial cells, sealed together to prevent the passage of toxic substances from the blood to the inner ear, by pericytes and perivascular-resident macrophage-like melanocyte. Recent Advances: There are various causes that lead to hearing loss, and among these are noise-induced and autoimmune hearing loss, ear disorders related to ototoxic medication, Ménière's disease, and age-related hearing loss. For all of these, major therapeutic interventions include drug-loaded nanoparticles, via intratympanic or intracochlear delivery. Critical Issues: Since many pathologies associated with hearing loss are characterized by a weakening of the BLB, in this review, the molecular mechanisms underlying the response to damage of BLB cellular components have been discussed. In addition, insight into the role of hormetic nutrients against hearing loss pathology is proposed. Future Directions: BLB cellular components of neurovascular cochlear unit play important physiological roles, owing to their impermeable function against all ototoxic substances that can induce damage. Studies are needed to investigate the cross talk occurring between these cellular components to exploit their possible role as novel targets for therapeutic interventions that may unravel future path based on the use of hormetic nutrients. Antioxid. Redox Signal. 40, 542-563.
Collapse
Affiliation(s)
- Alessia Cosentino
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Aleksandra Agafonova
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Sergio Modafferi
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Angela Trovato Salinaro
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Maria Scuto
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Luigi Maiolino
- Department of Medical, Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | | | - Edward J Calabrese
- Department of Environmental Health, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts, USA
| | - Gabriella Lupo
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Carmelina Daniela Anfuso
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| | - Vittorio Calabrese
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine; Surgical and Advanced Technologies "G. F. Ingrassia"; University of Catania, Catania, Italy
| |
Collapse
|
|
4
|
Mikłosz A, Chabowski A. Efficacy of adipose-derived mesenchymal stem cell therapy in the treatment of chronic micro- and macrovascular complications of diabetes. Diabetes Obes Metab 2024; 26:793-808. [PMID: 38073423 DOI: 10.1111/dom.15375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/23/2023] [Accepted: 11/05/2023] [Indexed: 02/06/2024]
Abstract
Diabetes mellitus is a highly prevalent disease characterized by hyperglycaemia that damages the vascular system, leading to micro- (retinopathy, neuropathy, nephropathy) and macrovascular diseases (cardiovascular disease). There are also secondary complications of diabetes (cardiomyopathy, erectile dysfunction or diabetic foot ulcers). Stem cell-based therapies have become a promising tool targeting diabetes symptoms and its chronic complications. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are of great importance because of their abundance, non-invasive isolation and no ethical limitations. Characteristics that make ADMSCs good candidates for cell-based therapy are their wide immunomodulatory properties and paracrine activities through the secretion of an array of growth factors, chemokines, cytokines, angiogenic factors and anti-apoptotic molecules. Besides, after transplantation, ADMSCs show great ex vivo expansion capacity and differentiation to other cell types, including insulin-producing cells, cardiomyocytes, chondrocytes, hepatocyte-like cells, neurons, endothelial cells, photoreceptor-like cells, or astrocytes. Preclinical studies have shown that ADMSC-based therapy effectively improved visual acuity, ameliorated polyneuropathy and foot ulceration, arrested the development and progression of diabetic kidney disease, or alleviated the diabetes-induced cardiomyocyte hypertrophy. However, despite the positive results obtained in animal models, there are still several challenges that need to be overcome before the results of preclinical studies can be translated into clinical applications. To date, there are several clinical trials or ongoing trials using ADMSCs in the treatment of diabetic complications, most of them in the treatment of diabetic foot ulcers. This narrative review summarizes the most recent outcomes on the usage of ADMSCs in the treatment of long-term complications of diabetes in both animal models and clinical trials.
Collapse
Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| |
Collapse
|
|
5
|
Yan D, Song Y, Zhang B, Cao G, Zhou H, Li H, Sun H, Deng M, Qiu Y, Yi W, Sun Y. Progress and application of adipose-derived stem cells in the treatment of diabetes and its complications. Stem Cell Res Ther 2024; 15:3. [PMID: 38167106 PMCID: PMC10763319 DOI: 10.1186/s13287-023-03620-0] [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: 08/01/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
Diabetes mellitus (DM) is a serious chronic metabolic disease that can lead to many serious complications, such as cardiovascular disease, retinopathy, neuropathy, and kidney disease. Once diagnosed with diabetes, patients need to take oral hypoglycemic drugs or use insulin to control blood sugar and slow down the progression of the disease. This has a significant impact on the daily life of patients, requiring constant monitoring of the side effects of medication. It also imposes a heavy financial burden on individuals, their families, and even society as a whole. Adipose-derived stem cells (ADSCs) have recently become an emerging therapeutic modality for DM and its complications. ADSCs can improve insulin sensitivity and enhance insulin secretion through various pathways, thereby alleviating diabetes and its complications. Additionally, ADSCs can promote tissue regeneration, inhibit inflammatory reactions, and reduce tissue damage and cell apoptosis. The potential mechanisms of ADSC therapy for DM and its complications are numerous, and its extensive regenerative and differentiation ability, as well as its role in regulating the immune system and metabolic function, make it a powerful tool in the treatment of DM. Although this technology is still in the early stages, many studies have already proven its safety and effectiveness, providing new treatment options for patients with DM or its complications. Although based on current research, ADSCs have achieved some results in animal experiments and clinical trials for the treatment of DM, further clinical trials are still needed before they can be applied in a clinical setting.
Collapse
Affiliation(s)
- Dongxu Yan
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Yujie Song
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Bing Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Guojie Cao
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Haitao Zhou
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Hong Li
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Hao Sun
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Meng Deng
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Yufeng Qiu
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China.
| | - Yang Sun
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, 127# Changlexi Road, Xi'an, 710032, China.
| |
Collapse
|
|
6
|
Wang Y, Zhang Y, Qu Y, Li S, Xi W, Liu B, Ye L. eIF4A3-mediated circEHMT1 regulation in retinal microvascular endothelial dysfunction in diabetic retinopathy. Microvasc Res 2024; 151:104612. [PMID: 37839527 DOI: 10.1016/j.mvr.2023.104612] [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: 07/24/2023] [Revised: 09/17/2023] [Accepted: 09/27/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND AND OBJECTIVE Literature has reported that circular RNAs (circRNAs) are crucially associated with diabetic retinopathy (DR). Furthermore, circEHMT1 has been identified to maintain endothelial cell barrier function. This study aimed to investigate the mechanisms that regulate aberrant circEHMT1 expression and its role in the pathogenesis of DR. METHODS In this study, retinal microvascular endothelial cells were exposed to a high glucose (HG) environment, and subsequently, tube formation and intercellular junction proteins were evaluated. Furthermore, the biological functions of circEHMT1 and its potential regulatory factor, eIF4A3, in microvascular endothelial cells under HG conditions were also assessed. In addition, the regulatory role of eIF4A3 on circEHMT1 expression was confirmed. Moreover, to elucidate the in vivo functions of eIF4A3 and circEHMT1, streptozotocin (STZ) was used to establish a DR model in rats. RESULTS It was revealed that HG condition decreased circEHMT1 and eIF4A3 expressions and reduced ZO-1, Claudin-5, and Occludin levels in retinal microvascular endothelial cells. Furthermore, it was observed that eIF4A3 could regulate the expression of circEHMT1. Overexpression of eIF4A3 or circEHMT1 under HG conditions improved endothelial cell injury and decreased tube-formation ability. Additionally, in the DR rat model, eIF4A3 overexpression restored circEHMT1 levels and ameliorated retinal vasculature changes. CONCLUSION Altogether, eIF4A3 regulates circEHMT1 expression, thereby affecting microvascular endothelial cell injury and tube formation. Further understanding the regulatory effect of eIF4A3 on circEHMT1 may provide novel therapeutic targets for DR.
Collapse
Affiliation(s)
- Yuan Wang
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China; Shenzhen Eye Institute, Shenzhen 518040, China
| | - Yongxin Zhang
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China; Shenzhen Eye Institute, Shenzhen 518040, China
| | - Yunhao Qu
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China
| | - Shixu Li
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China
| | - Wenqun Xi
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China; Shenzhen Eye Institute, Shenzhen 518040, China
| | - Beian Liu
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China
| | - Lin Ye
- Shenzhen Eye Hospital, Jinan University, Shenzhen 518040, China; Shenzhen Eye Institute, Shenzhen 518040, China.
| |
Collapse
|
|
7
|
Saha B, Roy A, Beltramo E, Sahoo OS. Stem cells and diabetic retinopathy: From models to treatment. Mol Biol Rep 2023; 50:4517-4526. [PMID: 36842153 DOI: 10.1007/s11033-023-08337-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 02/15/2023] [Indexed: 02/27/2023]
Abstract
Diabetic retinopathy is a common yet complex microvascular disease, caused as a complication of diabetes mellitus. Associated with hyperglycemia and subsequent metabolic abnormalities, advanced stages of the disease lead to fibrosis, subsequent visual impairment and blindness. Though clinical postmortems, animal and cell models provide information about the progression and prognosis of diabetic retinopathy, its underlying pathophysiology still needs a better understanding. In addition to it, the loss of pericytes, immature retinal angiogenesis and neuronal apoptosis portray the disease treatment to be challenging. Indulged with cell loss of both vascular and neuronal type cells, novel therapies like cell replacement strategies by various types of stem cells have been sightseen as a possible treatment of the disease. This review provides insight into the pathophysiology of diabetic retinopathy, current models used in modelling the disease, as well as the varied aspects of stem cells in generating three-dimensional retinal models. Further outlook on stem cell therapy and the future directions of stem cell treatment in diabetic retinopathy have also been contemplated.
Collapse
Affiliation(s)
- Bihan Saha
- National Institute of Technology Durgapur, Durgapur, 713209, West Bengal, India
| | - Akshita Roy
- Autonomous State Medical College, Fatehpur, 212601, Uttar Pradesh, India
| | - Elena Beltramo
- Department of Medical Sciences, University of Turin, 10124, Turin, Italy
| | - Om Saswat Sahoo
- National Institute of Technology Durgapur, Durgapur, 713209, West Bengal, India.
| |
Collapse
|
|
8
|
Tun SBB, Barathi VA. Akimba Proliferative Diabetic Retinopathy Model: Understanding Molecular Mechanism and Drug Screening for the Progression of Diabetic Retinopathy. Methods Mol Biol 2023; 2678:13-26. [PMID: 37326702 DOI: 10.1007/978-1-0716-3255-0_2] [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] [Indexed: 06/17/2023]
Abstract
As the prevalence of diabetes has reached epidemic proportions worldwide, diabetic retinopathy incidence is increasing rapidly. An advanced diabetic retinopathy (DR) stage can lead to a sight-threatening form. There is growing evidence showing diabetes causes a range of metabolic changes that subsequently lead to pathological modifications in the retina and retinal blood vessels. To understand the complex mechanism of the pathophysiology of DR, a precise model is not readily available. By crossbreeding the Akita and Kimba strains, a suitable proliferative DR model was acquired. This new Akimba strain manifests marked hyperglycemia and vascular changes, which resemble the early and advanced stage of DR.Here, we describe the breeding method, colony screening for experiments, and imaging techniques widely used to investigate the DR progression in this model. We elaborate step-by-step protocols to set up and perform fundus, fluorescein angiography, optical coherence tomography, and optical coherence tomography-angiogram to study retinal structural changes and vascular abnormalities. In addition, we show a method to label the leukocytes with fluorescence and laser speckle flowgraphy to examine the inflammation in the retina and retinal vessel blood flow speed, respectively. Lastly, we describe electroretinogram to evaluate the functional aspect of the DR transformations.
Collapse
Affiliation(s)
- Sai Bo Bo Tun
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore, Singapore
- Karolinska Institutet, Stockholm, Sweden
| | - Veluchamy Amutha Barathi
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore, Singapore.
- ACP in Ophthalmology & Visual Sciences, DUKE-NUS Graduate Medical School, Singapore, Singapore.
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
9
|
Hu Z, Liu Y, Yao Z, Chen L, Wang G, Liu X, Tian Y, Cao G. Stages of preadipocyte differentiation: biomarkers and pathways for extracellular structural remodeling. Hereditas 2022; 159:47. [PMID: 36572937 PMCID: PMC9793557 DOI: 10.1186/s41065-022-00261-w] [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: 06/09/2022] [Accepted: 12/05/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND This study utilized bioinformatics to analyze the underlying biological mechanisms involved in adipogenic differentiation, synthesis of the extracellular matrix (ECM), and angiogenesis during preadipocyte differentiation in human Simpson-Golabi-Behmel syndrome at different time points and identify targets that can potentially improve fat graft survival. RESULTS We analyzed two expression profiles from the Gene Expression Omnibus and identified differentially expressed genes (DEGs) at six different time points after the initiation of preadipocyte differentiation. Related pathways were identified using Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis (GSEA). We further constructed a protein-protein interaction (PPI) network and its central genes. The results showed that upregulated DEGs were involved in cell differentiation, lipid metabolism, and other cellular activities, while downregulated DEGs were associated with angiogenesis and development, ECM tissue synthesis, and intercellular and intertissue adhesion. GSEA provided a more comprehensive basis, including participation in and positive regulation of key pathways of cell metabolic differentiation, such as the "peroxisome proliferator-activated receptor signaling pathway" and the "adenylate-activated protein kinase signaling pathway," a key pathway that negatively regulates pro-angiogenic development, ECM synthesis, and adhesion. CONCLUSIONS We identified the top 20 hub genes in the PPI network, including genes involved in cell differentiation, ECM synthesis, and angiogenesis development, providing potential targets to improve the long-term survival rate of fat grafts. Additionally, we identified drugs that may interact with these targets to potentially improve fat graft survival.
Collapse
Affiliation(s)
- Zhihan Hu
- grid.412194.b0000 0004 1761 9803Department of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000 China
| | - Yi Liu
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Zongjiang Yao
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Liming Chen
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Gang Wang
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Xiaohui Liu
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Yafei Tian
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| | - Guangtong Cao
- grid.411294.b0000 0004 1798 9345Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, 730030 China
| |
Collapse
|
|
10
|
Song T, Zhu XY, Eirin A, Jiang Y, Krier JD, Tang H, Jordan KL, Lerman A, Lerman LO. Exogenous pericyte delivery protects the mouse kidney from chronic ischemic injury. Am J Physiol Renal Physiol 2022; 323:F527-F538. [PMID: 36049063 PMCID: PMC9602803 DOI: 10.1152/ajprenal.00064.2022] [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: 03/10/2022] [Revised: 08/19/2022] [Accepted: 08/19/2022] [Indexed: 12/14/2022] Open
Abstract
Pericytes are considered reparative mesenchymal stem cell-like cells, but their ability to ameliorate chronic ischemic kidney injury is unknown. We hypothesized that pericytes would exhibit renoprotective effects in murine renal artery stenosis (RAS). Porcine kidney-derived pericytes (5 × 105) or vehicle were injected into the carotid artery 2 wk after the induction of unilateral RAS in mice. The stenotic kidney glomerular filtration rate and tissue oxygenation were measured 2 wk later using magnetic resonance imaging. We subsequently compared kidney oxidative stress, inflammation, apoptosis, fibrosis, and systemic levels of oxidative and inflammatory cytokines. Treatment of xenogeneic pericytes ameliorated the RAS-induced loss of perfusion, glomerular filtration rate, and atrophy in stenotic kidneys and restored cortical and medullary oxygenation but did not blunt hypertension. Ex vivo, pericytes injection partially mitigated RAS-induced renal inflammation, fibrosis, oxidative stress, apoptosis, and senescence. Furthermore, coculture with pericytes in vitro protected pig kidney-1 tubular cells from injury. In conclusion, exogenous delivery of renal pericytes protects the poststenotic mouse kidney from ischemic injury, underscoring the therapeutic potential role of pericytes in subjects with ischemic kidney disease.NEW & NOTEWORTHY Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.
Collapse
Affiliation(s)
- Turun Song
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- Urology Department, Urology Research Institute, Organ Transplantation Center, West China Hospital, Sichuan University, Sichuan, China
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Yamei Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - James D Krier
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Kyra L Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular diseases, Mayo Clinic, Rochester, Minnesota
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
11
|
He S, Zhang Z, Peng X, Wu Y, Zhu Y, Wang L, Zhou H, Li T, Liu L. The protective effect of pericytes on vascular permeability after hemorrhagic shock and their relationship with Cx43. Front Physiol 2022; 13:948541. [PMID: 36262250 PMCID: PMC9576106 DOI: 10.3389/fphys.2022.948541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Vascular hyperpermeability is a complication of hemorrhagic shock. Pericytes (PCs) are a group of mural cells surrounded by microvessels that are located on the basolateral side of the endothelium. Previous studies have shown that damage to PCs contributes to the occurrence of many diseases such as diabetic retinopathy and myocardial infarction. Whether PCs can protect the vascular barrier function following hemorrhagic shock and the underlying mechanisms are unknown. A hemorrhagic shock rat model, Cx43 vascular endothelial cell (VEC)-specific knockdown mice, and VECs were used to investigate the role of PCs in vascular barrier function and their relationship with Cx43. The results showed that following hemorrhagic shock, the number of PCs in the microvessels was significantly decreased and was negatively associated with an increase in pulmonary and mesenteric vascular permeability. Exogenous infusion of PCs (106 cells per rat) colonized the microvessels and improved pulmonary and mesenteric vascular barrier function. Upregulation of Cx43 in PCs significantly increased the number of PCs colonizing the pulmonary vessels. In contrast, downregulation of Cx43 expression in PCs or knockout of Cx43 in VECs (Cx43 KO mice) significantly reduced PC colonization in pulmonary vessels in vivo and reduced direct contact formation between PCs and VECs in vitro. It has been suggested that PCs have an important protective effect on vascular barrier function in pulmonary and peripheral vessels following hemorrhagic shock. Cx43 plays an important role in the colonization of exogenous PCs in the microvessels. This finding provides a potential new shock treatment measure.
Collapse
Affiliation(s)
- Shuangshuang He
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
- Department of Pharmacy, Army Medical Center, Army Medical University, Chongqing, China
| | - Zisen Zhang
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Xiaoyong Peng
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Yue Wu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Yu Zhu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Li Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Henan Zhou
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
| | - Tao Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
- *Correspondence: Tao Li, ; Liangming Liu,
| | - Liangming Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Research Department, Army Medical Center, Army Medical University, Chongqing, China
- *Correspondence: Tao Li, ; Liangming Liu,
| |
Collapse
|
|
12
|
Hodges NA, Lampejo AO, Shang H, Rowe G, LeBlanc AJ, Katz AJ, Murfee WL. Viewing stromal vascular fraction de novo vessel formation and association with host microvasculature using the rat mesentery culture model. Microcirculation 2022; 29:e12758. [PMID: 35466504 PMCID: PMC9592675 DOI: 10.1111/micc.12758] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/26/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The objective of the study is to demonstrate the innovation and utility of mesenteric tissue culture for discovering the microvascular growth dynamics associated with adipose-derived stromal vascular fraction (SVF) transplantation. Understanding how SVF cells contribute to de novo vessel growth (i.e., neovascularization) and host network angiogenesis motivates the need to make observations at single-cell and network levels within a tissue. METHODS Stromal vascular fraction was isolated from the inguinal adipose of adult male Wistar rats, labeled with DiI, and seeded onto adult Wistar rat mesentery tissues. Tissues were then cultured in MEM + 10% FBS for 3 days and labeled for BSI-lectin to identify vessels. Alternatively, SVF and tissues from green fluorescent-positive (GFP) Sprague Dawley rats were used to track SVF derived versus host vasculature. RESULTS Stromal vascular fraction-treated tissues displayed a dramatically increased vascularized area compared to untreated tissues. DiI and GFP+ tracking of SVF identified neovascularization involving initial segment formation, radial outgrowth from central hub-like structures, and connection of segments. Neovascularization was also supported by the formation of segments in previously avascular areas. New segments characteristic of SVF neovessels contained endothelial cells and pericytes. Additionally, a subset of SVF cells displayed the ability to associate with host vessels and the presence of SVF increased host network angiogenesis. CONCLUSIONS The results showcase the use of the rat mesentery culture model as a novel tool for elucidating SVF cell transplant dynamics and highlight the impact of model selection for visualization.
Collapse
Affiliation(s)
- Nicholas A. Hodges
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Arinola O. Lampejo
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Hulan Shang
- Department of Plastic and Reconstructive Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Gabrielle Rowe
- Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
| | - Amanda Jo LeBlanc
- Department of Cardiovascular and Thoracic Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
| | - Adam J. Katz
- Department of Plastic and Reconstructive Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Walter L. Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| |
Collapse
|
|
13
|
Rowe G, Heng DS, Beare JE, Hodges NA, Tracy EP, Murfee WL, LeBlanc AJ. Stromal Vascular Fraction Reverses the Age-Related Impairment in Revascularization following Injury. J Vasc Res 2022; 59:343-357. [PMID: 36075199 PMCID: PMC9780192 DOI: 10.1159/000526002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/06/2022] [Indexed: 12/31/2022] Open
Abstract
Adipose-derived stromal vascular fraction (SVF) has emerged as a potential regenerative therapy, but few studies utilize SVF in a setting of advanced age. Additionally, the specific cell population in SVF providing therapeutic benefit is unknown. We hypothesized that aging would alter the composition of cell populations present in SVF and its ability to promote angiogenesis following injury, a mechanism that is T cell-mediated. SVF isolated from young and old Fischer 344 rats was examined with flow cytometry for cell composition. Mesenteric windows from old rats were isolated following exteriorization-induced (EI) hypoxic injury and intravenous injection of one of four cell therapies: (1) SVF from young or (2) old donors, (3) SVF from old donors depleted of or (4) enriched for T cells. Advancing age increased the SVF T-cell population but reduced revascularization following injury. Both young and aged SVF incorporated throughout the host mesenteric microvessels, but only young SVF significantly increased vascular area following EI. This study highlights the effect of donor age on SVF angiogenic efficacy and demonstrates how the ex vivo mesenteric-window model can be used in conjunction with SVF therapy to investigate its contribution to angiogenesis.
Collapse
Affiliation(s)
- Gabrielle Rowe
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA,
- Department of Physiology, University of Louisville, Louisville, Kentucky, USA,
| | - David S Heng
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
| | - Jason E Beare
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, USA
| | - Nicholas A Hodges
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Evan P Tracy
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
- Department of Physiology, University of Louisville, Louisville, Kentucky, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Amanda J LeBlanc
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
- Department of Cardiovascular and Thoracic Surgery, University of Louisville, Louisville, Kentucky, USA
| |
Collapse
|
|
14
|
Lechner J, Medina RJ, Lois N, Stitt AW. Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina. Stem Cell Res Ther 2022; 13:388. [PMID: 35907890 PMCID: PMC9338609 DOI: 10.1186/s13287-022-03073-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/20/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Diabetic retinopathy, a major complication of diabetes mellitus, is a leading cause of sigh-loss in working age adults. Progressive loss of integrity of the retinal neurovascular unit is a central element in the disease pathogenesis. Retinal ischemia and inflammatory processes drive interrelated pathologies such as blood retinal barrier disruption, fluid accumulation, gliosis, neuronal loss and/or aberrant neovascularisation. Current treatment options are somewhat limited to late-stages of the disease where there is already significant damage to the retinal architecture arising from degenerative, edematous and proliferative pathology. New preventive and interventional treatments to target early vasodegenerative and neurodegenerative stages of the disease are needed to ensure avoidance of sight-loss. MAIN BODY Historically, diabetic retinopathy has been considered a primarily microvascular disease of the retina and clinically it is classified based on the presence and severity of vascular lesions. It is now known that neurodegeneration plays a significant role during the pathogenesis. Loss of neurons has been documented at early stages in pre-clinical models as well as in individuals with diabetes and, in some, even prior to the onset of clinically overt diabetic retinopathy. Recent studies suggest that some patients have a primarily neurodegenerative phenotype. Retinal pigment epithelial cells and the choroid are also affected during the disease pathogenesis and these tissues may also need to be addressed by new regenerative treatments. Most stem cell research for diabetic retinopathy to date has focused on addressing vasculopathy. Pre-clinical and clinical studies aiming to restore damaged vasculature using vasoactive progenitors including mesenchymal stromal/stem cells, adipose stem cells, CD34+ cells, endothelial colony forming cells and induced pluripotent stem cell derived endothelial cells are discussed in this review. Stem cells that could replace dying neurons such as retinal progenitor cells, pluripotent stem cell derived photoreceptors and ganglion cells as well as Müller stem cells are also discussed. Finally, challenges of stem cell therapies relevant to diabetic retinopathy are considered. CONCLUSION Stem cell therapies hold great potential to replace dying cells during early and even late stages of diabetic retinopathy. However, due to the presence of different phenotypes, selecting the most suitable stem cell product for individual patients will be crucial for successful treatment.
Collapse
Affiliation(s)
- Judith Lechner
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK.
| | - Reinhold J Medina
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Noemi Lois
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK.
| |
Collapse
|
|
15
|
Yu H, Commander CW, Stavas JM. Stem Cell-Based Therapies: What Interventional Radiologists Need to Know. Semin Intervent Radiol 2021; 38:523-534. [PMID: 34853498 DOI: 10.1055/s-0041-1736657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
As the basic units of biological organization, stem cells and their progenitors are essential for developing and regenerating organs and tissue systems using their unique self-renewal capability and differentiation potential into multiple cell lineages. Stem cells are consistently present throughout the entire human development, from the zygote to adulthood. Over the past decades, significant efforts have been made in biology, genetics, and biotechnology to develop stem cell-based therapies using embryonic and adult autologous or allogeneic stem cells for diseases without therapies or difficult to treat. Stem cell-based therapies require optimum administration of stem cells into damaged organs to promote structural regeneration and improve function. Maximum clinical efficacy is highly dependent on the successful delivery of stem cells to the target tissue. Direct image-guided locoregional injections into target tissues offer an option to increase therapeutic outcomes. Interventional radiologists have the opportunity to perform a key role in delivering stem cells more efficiently using minimally invasive techniques. This review discusses the types and sources of stem cells and the current clinical applications of stem cell-based therapies. In addition, the regulatory considerations, logistics, and potential roles of interventional Radiology are also discussed with the review of the literature.
Collapse
Affiliation(s)
- Hyeon Yu
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.,ProKidney LLC, Winston Salem, North Carolina
| | - Clayton W Commander
- Division of Vascular and Interventional Radiology, Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Joseph M Stavas
- Department of Radiology, Creighton University School of Medicine, Omaha, Nebraska
| |
Collapse
|
|
16
|
Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells. Int J Mol Sci 2021; 22:ijms221910890. [PMID: 34639228 PMCID: PMC8509224 DOI: 10.3390/ijms221910890] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell-cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo.
Collapse
|
|
17
|
Association between diabetic retinopathy and polymorphisms of cytokine genes: a systematic review and meta-analysis. Int Ophthalmol 2021; 42:349-361. [PMID: 34432176 DOI: 10.1007/s10792-021-02011-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 08/13/2021] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Diabetic retinopathy (DR) is a medical condition caused by damage to the blood vessels of retina tissue due to diabetes mellitus. DR leads to injury in neural and vascular structures and is reported to be significantly influenced by inflammation and inflammatory mediators like cytokines. In this study, a systematic review and meta-analysis were performed to analyze the association between cytokine gene polymorphisms and DR. METHODS We identified relevant studies from Scopus, PubMed, and Google scholar databases. Allele and genotype frequencies were pooled. Heterogeneity and publication bias were explored. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the relation. RESULTS A total of 3337 cases and 4945 controls in 19 eligible studies were included in the meta-analysis. Overall, results indicated the negative association between the cytokine gene polymorphisms and DR susceptibility in the allelic model (IFN-γ (rs2430561): OR 0.64, [CI]: 0.5 to 0.82; and TGF-β (rs1800471): [OR] = 0.15, [CI]: 0.03 to 0.79); and also, in the dominant model (IFN-γ (rs2430561): OR = 0.4, [CI]: 0.22 to 0.75; and TGF-β (rs1800471): OR = 0.14, [CI]: 0.05 to 0.4). CONCLUSION The present study suggests that IFN-γ (rs2430561) and TGF-β (rs1800471) polymorphisms are associated with decreased susceptibility to DR.
Collapse
|
|
18
|
Adak S, Magdalene D, Deshmukh S, Das D, Jaganathan BG. A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases. Stem Cell Rev Rep 2021; 17:1154-1173. [PMID: 33410097 PMCID: PMC7787584 DOI: 10.1007/s12015-020-10090-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal Stem Cells (MSCs) have been studied extensively for the treatment of several retinal diseases. The therapeutic potential of MSCs lies in its ability to differentiate into multiple lineages and secretome enriched with immunomodulatory, anti-angiogenic and neurotrophic factors. Several studies have reported the role of MSCs in repair and regeneration of the damaged retina where the secreted factors from MSCs prevent retinal degeneration, improve retinal morphology and function. MSCs also donate mitochondria to rescue the function of retinal cells and exosomes secreted by MSCs were found to have anti-apoptotic and anti-inflammatory effects. Based on several promising results obtained from the preclinical studies, several clinical trials were initiated to explore the potential advantages of MSCs for the treatment of retinal diseases. This review summarizes the various properties of MSCs that help to repair and restore the damaged retinal cells and its potential for the treatment of retinal degenerative diseases.
Collapse
Affiliation(s)
- Sanjucta Adak
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Damaris Magdalene
- Department of Strabismus, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Saurabh Deshmukh
- Department of Strabismus, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Dipankar Das
- Department of Pathology, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
| |
Collapse
|
|
19
|
Thomas HM, Ahangar P, Fitridge R, Kirby GTS, Mills SJ, Cowin AJ. Plasma-polymerized pericyte patches improve healing of murine wounds through increased angiogenesis and reduced inflammation. Regen Biomater 2021; 8:rbab024. [PMID: 34221447 PMCID: PMC8242226 DOI: 10.1093/rb/rbab024] [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: 02/16/2021] [Revised: 04/13/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Pericytes have the potential to be developed as a cell therapy for the treatment of wounds; however, the efficacy of any cell therapy relies on the successful delivery of intact and functioning cells. Here, the effect of delivering pericytes on wound repair was assessed alongside the development of a surface-functionalized pericyte patch. Plasma polymerization (PP) was used to functionalize the surface of silicone patches with heptylamine (HA) or acrylic acid (AA) monomers. Human pericytes were subsequently delivered to murine excisional wounds by intradermal injection or using the pericyte-laden patches and the comparative effects on wound healing, inflammation and revascularization determined. The AA surface provided the superior transfer of the cells to de-epidermized dermis. Excisional murine wounds treated either with pericytes injected directly into the wound or with the pericyte-laden AA patches showed improved healing with decreased neutrophil infiltration and reduced numbers of macrophages in the wounds. Pericyte delivery also enhanced angiogenesis through a mechanism independent of VEGF signalling. Pericytes, when delivered to wounds, improved healing responses by dampening inflammation and promoting angiogenesis. Delivery of pericytes using PP-AA-functionalized patches was equally as effective as direct injection of pericytes into wounds. Pericyte-functionalized dressings may therefore be a clinically relevant approach for the treatment of wounds.
Collapse
Affiliation(s)
- Hannah M Thomas
- Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide SA 5000, Australia
| | - Parinaz Ahangar
- Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide SA 5000, Australia
| | - Robert Fitridge
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide SA 5005, Australia
| | - Giles T S Kirby
- Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia
| | - Stuart J Mills
- Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide SA 5000, Australia
| | - Allison J Cowin
- Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide SA 5000, Australia
| |
Collapse
|
|
20
|
Mannino G, Russo C, Longo A, Anfuso CD, Lupo G, Lo Furno D, Giuffrida R, Giurdanella G. Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases. World J Stem Cells 2021; 13:632-644. [PMID: 34249232 PMCID: PMC8246249 DOI: 10.4252/wjsc.v13.i6.632] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based treatments have been extensively explored in the last few decades to develop therapeutic strategies aimed at providing effective alternatives for those human pathologies in which surgical or pharmacological therapies produce limited effects. Among stem cells of different sources, mesenchymal stem cells (MSCs) offer several advantages, such as the absence of ethical concerns, easy harvesting, low immunogenicity and reduced tumorigenesis risks. Other than a multipotent differentiation ability, MSCs can release extracellular vesicles conveying proteins, mRNA and microRNA. Thanks to these properties, new therapeutic approaches have been designed for the treatment of various pathologies, including ocular diseases. In this review, the use of different MSCs and different administration strategies are described for the treatment of diabetic retinopathy, glaucoma, and retinitis pigmentosa. In a large number of investigations, positive results have been obtained by in vitro experiments and by MSC administration in animal models. Most authors agree that beneficial effects are likely related to MSC paracrine activity. Based on these considerations, many clinical trials have already been carried out. Overall, although some adverse effects have been described, promising outcomes are reported. It can be assumed that in the near future, safer and more effective protocols will be developed for more numerous clinical applications to improve the quality of life of patients affected by eye diseases.
Collapse
Affiliation(s)
- Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Anna Longo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Carmelina Daniela Anfuso
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Gabriella Lupo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy.
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| |
Collapse
|
|
21
|
Coco-Martin RM, Pastor-Idoate S, Pastor JC. Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges. Pharmaceutics 2021; 13:pharmaceutics13060865. [PMID: 34208272 PMCID: PMC8230855 DOI: 10.3390/pharmaceutics13060865] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce a localized retinal detachment to perform the subretinal placement of the transplanted cell; (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.
Collapse
Affiliation(s)
- Rosa M. Coco-Martin
- Instituto de Oftalmobiologia Aplicada (IOBA), Medical School, Universidad de Valladolid, 47011 Valladolid, Spain; (S.P.-I.); (J.C.P.)
- National Institute of Health Carlos III (ISCIII), (RETICS) Cooperative Health Network for Research in Ophthalmology (Oftared), 28040 Madrid, Spain
- Correspondence: ; Tel.: +34-983423559
| | - Salvador Pastor-Idoate
- Instituto de Oftalmobiologia Aplicada (IOBA), Medical School, Universidad de Valladolid, 47011 Valladolid, Spain; (S.P.-I.); (J.C.P.)
- National Institute of Health Carlos III (ISCIII), (RETICS) Cooperative Health Network for Research in Ophthalmology (Oftared), 28040 Madrid, Spain
- Department of Ophthalmology, Hospital Clinico Universitario of Valladolid, 47003 Valladolid, Spain
| | - Jose Carlos Pastor
- Instituto de Oftalmobiologia Aplicada (IOBA), Medical School, Universidad de Valladolid, 47011 Valladolid, Spain; (S.P.-I.); (J.C.P.)
- National Institute of Health Carlos III (ISCIII), (RETICS) Cooperative Health Network for Research in Ophthalmology (Oftared), 28040 Madrid, Spain
- Department of Ophthalmology, Hospital Clinico Universitario of Valladolid, 47003 Valladolid, Spain
- Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Fundacion del Instituto de Estudios de Ciencias de la Salud de Castilla y León (ICSCYL), 42002 Soria, Spain
| |
Collapse
|
|
22
|
Effects of High Glucose Concentration on Pericyte-Like Differentiated Human Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22094604. [PMID: 33925714 PMCID: PMC8125146 DOI: 10.3390/ijms22094604] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/19/2021] [Accepted: 04/24/2021] [Indexed: 02/07/2023] Open
Abstract
A pericyte-like differentiation of human adipose-derived mesenchymal stem cells (ASCs) was tested in in vitro experiments for possible therapeutic applications in cases of diabetic retinopathy (DR) to replace irreversibly lost pericytes. For this purpose, pericyte-like ASCs were obtained after their growth in a specific pericyte medium. They were then cultured in high glucose conditions to mimic the altered microenvironment of a diabetic eye. Several parameters were monitored, especially those particularly affected by disease progression: cell proliferation, viability and migration ability; reactive oxygen species (ROS) production; inflammation-related cytokines and angiogenic factors. Overall, encouraging results were obtained. In fact, even after glucose addition, ASCs pre-cultured in the pericyte medium (pmASCs) showed high proliferation rate, viability and migration ability. A considerable increase in mRNA expression levels of the anti-inflammatory cytokines transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) was observed, associated with reduction in ROS production, and mRNA expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and angiogenic factors. Finally, a pmASC-induced better organization of tube-like formation by retinal endothelial cells was observed in three-dimensional co-culture. The pericyte-like ASCs obtained in these experiments represent a valuable tool for the treatment of retinal damages occurring in diabetic patients.
Collapse
|
|
23
|
Antonetti DA, Silva PS, Stitt AW. Current understanding of the molecular and cellular pathology of diabetic retinopathy. Nat Rev Endocrinol 2021; 17:195-206. [PMID: 33469209 PMCID: PMC9053333 DOI: 10.1038/s41574-020-00451-4] [Citation(s) in RCA: 288] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/18/2020] [Indexed: 01/19/2023]
Abstract
Diabetes mellitus has profound effects on multiple organ systems; however, the loss of vision caused by diabetic retinopathy might be one of the most impactful in a patient's life. The retina is a highly metabolically active tissue that requires a complex interaction of cells, spanning light sensing photoreceptors to neurons that transfer the electrochemical signal to the brain with support by glia and vascular tissue. Neuronal function depends on a complex inter-dependency of retinal cells that includes the formation of a blood-retinal barrier. This dynamic system is negatively affected by diabetes mellitus, which alters normal cell-cell interactions and leads to profound vascular abnormalities, loss of the blood-retinal barrier and impaired neuronal function. Understanding the normal cell signalling interactions and how they are altered by diabetes mellitus has already led to novel therapies that have improved visual outcomes in many patients. Research highlighted in this Review has led to a new understanding of retinal pathophysiology during diabetes mellitus and has uncovered potential new therapeutic avenues to treat this debilitating disease.
Collapse
Affiliation(s)
- David A Antonetti
- Department of Ophthalmology and Visual Sciences, Department of Molecular and Integrative Physiology, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA.
| | - Paolo S Silva
- Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
- Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, USA
| | - Alan W Stitt
- Centre for Experimental Medicine, Queen's University, Belfast, UK
| |
Collapse
|
|
24
|
Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials. Cells 2021; 10:cells10030588. [PMID: 33799995 PMCID: PMC8001847 DOI: 10.3390/cells10030588] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/13/2022] Open
Abstract
Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality of vision or even blindness worldwide. However, despite considerable efforts, the treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of a particular patient, expanded in vitro and used as the autologous cells. MSCs possess potent immunoregulatory properties and can inhibit a harmful inflammatory reaction in the diseased retina. By the production of numerous growth and neurotrophic factors, they support the survival and growth of retinal cells. In addition, MSCs can protect retinal cells by antiapoptotic properties and could contribute to the regeneration of the diseased retina by their ability to differentiate into various cell types, including the cells of the retina. All of these properties indicate the potential of MSCs for the therapy of diseased retinas. This view is supported by the recent results of numerous experimental studies in different preclinical models. Here we provide an overview of the therapeutic properties of MSCs, and their use in experimental models of retinal diseases and in clinical trials.
Collapse
|
|
25
|
Al-Ghadban S, Bunnell BA. Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential. Physiology (Bethesda) 2021; 35:125-133. [PMID: 32027561 DOI: 10.1152/physiol.00021.2019] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ASCs) can self-renew and differentiate along multiple cell lineages. ASCs are also potently anti-inflammatory due to their inherent ability to regulate the immune system by secreting anti-inflammatory cytokines and growth factors that play a crucial role in the pathology of many diseases, including multiple sclerosis, diabetes mellitus, Crohn's, SLE, and graft-versus-host disease. The immunomodulatory effects and mechanisms of action of ASCs on pathological conditions are reviewed here.
Collapse
Affiliation(s)
- Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bruce A Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana
| |
Collapse
|
|
26
|
Payne LB, Darden J, Suarez-Martinez AD, Zhao H, Hendricks A, Hartland C, Chong D, Kushner EJ, Murfee WL, Chappell JC. Pericyte migration and proliferation are tightly synchronized to endothelial cell sprouting dynamics. Integr Biol (Camb) 2021; 13:31-43. [PMID: 33515222 DOI: 10.1093/intbio/zyaa027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/13/2020] [Accepted: 12/26/2020] [Indexed: 01/17/2023]
Abstract
Pericytes are critical for microvascular stability and maintenance, among other important physiological functions, yet their involvement in vessel formation processes remains poorly understood. To gain insight into pericyte behaviors during vascular remodeling, we developed two complementary tissue explant models utilizing 'double reporter' animals with fluorescently-labeled pericytes and endothelial cells (via Ng2:DsRed and Flk-1:eGFP genes, respectively). Time-lapse confocal imaging of active vessel remodeling within adult connective tissues and embryonic skin revealed a subset of pericytes detaching and migrating away from the vessel wall. Vessel-associated pericytes displayed rapid filopodial sampling near sprouting endothelial cells that emerged from parent vessels to form nascent branches. Pericytes near angiogenic sprouts were also more migratory, initiating persistent and directional movement along newly forming vessels. Pericyte cell divisions coincided more frequently with elongating endothelial sprouts, rather than sprout initiation sites, an observation confirmed with in vivo data from the developing mouse brain. Taken together, these data suggest that (i) pericyte detachment from the vessel wall may represent an important physiological process to enhance endothelial cell plasticity during vascular remodeling, and (ii) pericyte migration and proliferation are highly synchronized with endothelial cell behaviors during the coordinated expansion of a vascular network.
Collapse
Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA
| | - Jordan Darden
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Ariana D Suarez-Martinez
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Huaning Zhao
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Alissa Hendricks
- Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Caitlin Hartland
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA
| | - Diana Chong
- Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Erich J Kushner
- Department of Biological Sciences, University of Denver, Denver, CO 80208 USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - John C Chappell
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute, Roanoke, VA 24014, USA.,Graduate Program in Translational Biology, Medicine, & Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.,Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.,Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
| |
Collapse
|
|
27
|
Wang L, Xiong X, Zhang L, Shen J. Neurovascular Unit: A critical role in ischemic stroke. CNS Neurosci Ther 2021; 27:7-16. [PMID: 33389780 PMCID: PMC7804897 DOI: 10.1111/cns.13561] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022] Open
Abstract
Ischemic stroke (IS), a common cerebrovascular disease, results from a sudden blockage of a blood vessel in the brain, thereby restricting blood supply to the area in question, and making a significantly negative impact on human health. Unfortunately, current treatments, that are mainly based on a recanalization of occluded blood vessels, are insufficient or inaccessible to many stroke patients. Recently, the profound influence of the neurovascular unit (NVU) on recanalization and the prognosis of IS have become better understood; in‐depth studies of the NVU have also provided novel approaches for IS treatment. In this article, we review the intimate connections between the changes in the NVU and IS outcomes, and discuss possible new management strategies having practical significance to IS. We discuss the concept of the NVU, as well as its roles in IS blood‐brain barrier regulation, cell preservation, inflammatory immune response, and neurovascular repair. Besides, we also summarize the influence of noncoding RNAs in NVU, and IS therapies targeting the NVU. We conclude that both the pathophysiological and neurovascular repair processes of IS are strongly associated with the homeostatic state of the NVU and that further research into therapies directed at the NVU could expand the range of treatments available for IS.
Collapse
Affiliation(s)
- Liyun Wang
- Department of Neurosurgery, Shengzhou People's Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shengzhou, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Luyuan Zhang
- Department of Neurosurgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Shen
- Department of Neurosurgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
28
|
Li XJ, Li CY, Bai D, Leng Y. Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis. Neural Regen Res 2021; 16:172-178. [PMID: 32788473 PMCID: PMC7818871 DOI: 10.4103/1673-5374.286974] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Stem cells have been confirmed to be involved in the occurrence and development of diabetic retinopathy; however, the underlying mechanisms remain unclear. In this study, we used Citespace software to visually analyze 552 articles exploring the stem cell-based treatment of diabetic retinopathy over the past 20 years, which were included in the Web of Science Core Collection. We found the following: (1) a co-citation analysis of the references cited by all 552 articles indicated 15 clusters. In cluster #0, representing the stem cell field, some highly cited landmark studies emerged between 2009–2013. For example, endothelial progenitor cells and diabetic retinopathy gradually received the full attention of scholars, in terms of their relationship and therapeutic prospects. Some researchers also verified the potential of adipose-derived stem cells to differentiate into stable retinal perivascular cells, using a variety of animal models of retinal vascular disease. All of these achievements provided references for the subsequent stem cell research. (2) An analysis of popular keywords among the 552 articles revealed that, during the past 20 years, a relative increase in basic research articles examining stem cells and endothelial progenitor cells for the treatment of diabetic retinopathy was observed. The contents of these articles primarily involved the expression of vascular endothelial growth factor, vascular regeneration, oxidative stress, and inflammatory response. (3) A burst analysis of keywords used in the 552 articles indicated that genetic and cytological research regarding the promotion of angiogenesis was an issue of concern from 2001 to 2012, including several studies addressing the expression of various growth factor genes; from 2014 to 2020, mouse models of diabetic retinopathy were recognized as mature animal models, and the most recent research has focused on macular degeneration, macular edema, neurodegeneration, and inflammatory changes in diabetic animal models. (4) Globally, the current authoritative studies have focused on basic research towards the stem cell treatment of diabetic retinopathy. Existing clinical studies are of low quality and have insufficient evidence levels, and their findings have not yet been widely accepted in clinical practice. Major challenges during stem cell transplantation remain, including stem cell heterogeneity, cell delivery, and the effective homing of stem cells to damaged tissue. However, clinical trials examining potential stem cell-based treatments of diabetic retinopathy, including the use of pluripotent stem cells, retinal pigment epithelial cells, bone marrow mesenchymal stem cells, and endothelial progenitor cells, are currently ongoing, and high-quality clinical evidence is likely to appear in the future, to promote clinical transformation.
Collapse
Affiliation(s)
- Xiang-Jun Li
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Chun-Yan Li
- Department of Endocrinology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Dan Bai
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Ying Leng
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| |
Collapse
|
|
29
|
Mannino G, Gennuso F, Giurdanella G, Conti F, Drago F, Salomone S, Furno DL, Bucolo C, Giuffrida R. Pericyte-like differentiation of human adipose-derived mesenchymal stem cells: An in vitro study. World J Stem Cells 2020; 12:1152-1170. [PMID: 33178398 PMCID: PMC7596446 DOI: 10.4252/wjsc.v12.i10.1152] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/18/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adipose-derived mesenchymal stem cells (ASCs) are characterized by long-term self-renewal and a high proliferation rate. Under adequate conditions, they may differentiate into cells belonging to mesodermal, endodermal or ectodermal lineages. Pericytes support endothelial cells and play an important role in stabilizing the vessel wall at the microcirculation level. The loss of pericytes, as occurs in diabetic retinopathy, results in a breakdown of the blood-retina barrier (BRB) and infiltration of inflammatory cells. In this context, the use of pericyte-like differentiated ASCs may represent a valuable therapeutic strategy for restoring BRB damage. AIM To test in vitro strategies to obtain pericyte-like differentiation of human ASCs (hASCs). METHODS Different culture conditions were tested: hASCs cultured in a basal medium supplemented with transforming growth factor β1; and hASCs cultured in a specific pericyte medium (PM-hASCs). In a further sample, pericyte growth supplement was omitted from the PM. In addition, cultures of human retinal pericytes (hRPCs) were used for comparison. Pericyte-like differentiation of hASCs was tested by immunocytochemical staining and western blotting to evaluate the expression of α-smooth muscle actin (α-SMA) and neural/glial antigen 2 (NG2). Interactions between human retinal endothelial cells (hRECs) and different groups of hASCs were investigated in co-culture experiments. In these cases, the expression of typical junctional proteins such as vascular endothelial-Cadherin, zonula occludens-1 and Occludin were assessed in hRECs. In an in vitro model of the BRB, values of trans-endothelial electrical resistance were measured when hRECs were co-cultured with various groups of pretreated hASCs. The values observed were compared with co-cultures of hRECs and hRPCs as well as with cultures of hRECs alone. Three-dimensional co-cultures of hRECs and hRPCs or pericyte-like hASCs in Matrigel were designed to assess their reciprocal localization. RESULTS After 3-6 d of culture, α-SMA and NG2 immunocytochemistry showed that the closest pericyte-like phenotype was observed when hASCs were cultured in Pericyte Medium (PM-hASCs). In particular, α-SMA immunoreactivity, already visible at the basal level in pericytes and ASCs, was strongly increased only when transforming growth factor was added to the culture medium. NG2 expression, almost undetectable in most conditions, was substantially increased only in PM-hASCs. Immunocytochemical results were confirmed by western blot analysis. The presence of pericyte growth supplement seems to increase NG2 expression rather than α-SMA, in agreement with its role in maintaining pericytes in the proliferative state. In co-culture experiments, immunoreactivity of vascular endothelial-Cadherin, zonula occludens-1 and Occludin was considerably increased in hRECs when hRPCs or PM-hASCs were also present. Supporting results were found by trans-endothelial electrical resistance measurements, gathered at 3 and 6 d of co-culture. The highest resistance values were obtained when hRECs were co-cultured with hRPCs or PM-hASCs. The pericyte-like phenotype of PM-hASCs was also confirmed in three-dimensional co-cultures in Matrigel, where PM-hASCs and hRPCs similarly localized around the tubular formations made by hRECs. CONCLUSION PM-hASCs seem able to strengthen the intercellular junctions between hRECs, likely reinforcing the BRB; thus, hASC-based therapeutic approaches may be developed to restore the integrity of retinal microcirculation.
Collapse
Affiliation(s)
- Giuliana Mannino
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Florinda Gennuso
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Giovanni Giurdanella
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Federica Conti
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Filippo Drago
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Salvatore Salomone
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Debora Lo Furno
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy.
| | - Claudio Bucolo
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Rosario Giuffrida
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| |
Collapse
|
|
30
|
O'Hara L, Christian HC, Jeffery N, Le Tissier P, Smith LB. Characterisation of a mural cell network in the murine pituitary gland. J Neuroendocrinol 2020; 32:e12903. [PMID: 32959418 DOI: 10.1111/jne.12903] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 08/03/2020] [Accepted: 08/21/2020] [Indexed: 11/29/2022]
Abstract
The anterior and intermediate lobes of the pituitary are composed of endocrine cells, as well as vasculature and supporting cells, such as folliculostellate cells. Folliculostellate cells form a network with several postulated roles in the pituitary, including production of paracrine signalling molecules and cytokines, coordination of endocrine cell hormone release, phagocytosis, and structural support. Folliculostellate cells in rats are characterised by expression of S100B protein, and in humans by glial fibrillary acid protein. However, there is evidence for another network of supporting cells in the anterior pituitary that has properties of mural cells, such as vascular smooth muscle cells and pericytes. The present study aims to characterise the distribution of cells that express the mural cell marker platelet derived growth factor receptor beta (PDGFRβ) in the mouse pituitary and establish whether these cells are folliculostellate. By immunohistochemical localisation, we determine that approximately 80% of PDGFRβ+ cells in the mouse pituitary have a non-perivascular location and 20% are pericytes. Investigation of gene expression in a magnetic cell sorted population of PDGFRβ+ cells shows that, despite a mostly non-perivascular location, this population is enriched for mural cell markers but not enriched for rat or human folliculostellate cell markers. This is confirmed by immunohistochemistry. The present study concludes that a mural cell network is present throughout the anterior pituitary of the mouse and that this population does not express well-characterised human or rat folliculostellate cell markers.
Collapse
Affiliation(s)
- Laura O'Hara
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | - Helen C Christian
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Nathan Jeffery
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | - Paul Le Tissier
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Lee B Smith
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
- School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, Australia
| |
Collapse
|
|
31
|
Ray HC, Corliss BA, Bruce AC, Kesting S, Dey P, Mansour J, Seaman SA, Smolko CM, Mathews C, Dey BK, Owens GK, Peirce SM, Yates PA. Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis. Sci Rep 2020; 10:15808. [PMID: 32978500 PMCID: PMC7519078 DOI: 10.1038/s41598-020-72875-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 08/10/2020] [Indexed: 12/29/2022] Open
Abstract
Retinal diseases are frequently characterized by the accumulation of excessive scar tissue found throughout the neural retina. However, the pathophysiology of retinal fibrosis remains poorly understood, and the cell types that contribute to the fibrotic response are incompletely defined. Here, we show that myofibroblast differentiation of mural cells contributes directly to retinal fibrosis. Using lineage tracing technology, we demonstrate that after chemical ocular injury, Myh11+ mural cells detach from the retinal microvasculature and differentiate into myofibroblasts to form an epiretinal membrane. Inhibition of TGFβR attenuates Myh11+ retinal mural cell myofibroblast differentiation, and diminishes the subsequent formation of scar tissue on the surface of the retina. We demonstrate retinal fibrosis within a murine model of oxygen-induced retinopathy resulting from the intravitreal injection of adipose Myh11-derived mesenchymal stem cells, with ensuing myofibroblast differentiation. In this model, inhibiting TGFβR signaling does not significantly alter myofibroblast differentiation and collagen secretion within the retina. This work shows the complexity of retinal fibrosis, where scar formation is regulated both by TGFβR and non-TGFβR dependent processes involving mural cells and derived mesenchymal stem cells. It also offers a cautionary note on the potential deleterious, pro-fibrotic effects of exogenous MSCs once intravitreally injected into clinical patients.
Collapse
Affiliation(s)
- H Clifton Ray
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Bruce A Corliss
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Anthony C Bruce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Sam Kesting
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Paromita Dey
- The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - Jennifer Mansour
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - Scott A Seaman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Christian M Smolko
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Corbin Mathews
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Bijan K Dey
- The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - Gary K Owens
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
| | - Shayn M Peirce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Paul A Yates
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
- Department of Ophthalmology, University of Virginia, PO Box 800715, Charlottesville, VA, 22908, USA.
| |
Collapse
|
|
32
|
Kutlutürk Karagöz I, Allahverdiyev A, Bağırova M, Abamor EŞ, Dinparvar S. Current Approaches in Treatment of Diabetic Retinopathy and Future Perspectives. J Ocul Pharmacol Ther 2020; 36:487-496. [DOI: 10.1089/jop.2019.0137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Işıl Kutlutürk Karagöz
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
- Department of Ophthalmology, Ümraniye Trn. And Rch. Hospital, Istanbul, Turkey
| | - Adil Allahverdiyev
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Melehat Bağırova
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Emrah Şefik Abamor
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| | - Sahar Dinparvar
- Depatment of Bioengineering, Yıldız Technical University, Istanbul, Turkey
| |
Collapse
|
|
33
|
Mayo JN, Kauer SD, Brumley MR, Bearden SE. Pericytes improve locomotor recovery after spinal cord injury in male and female neonatal rats. Microcirculation 2020; 27:e12646. [PMID: 32608116 DOI: 10.1111/micc.12646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/06/2020] [Accepted: 06/23/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE It is not known how activation of the hypoxia-inducible factor (HIF) pathway in pericytes, cells of the microvascular wall, influences new capillary growth. We tested the hypothesis that HIF-activated pericytes promote angiogenesis in a neonatal model of spinal cord injury (SCI). METHODS Human placental pericytes stimulated with cobalt chloride and naïve pericytes were injected into the site of a thoracic hemi-section of the spinal cord in rat pups on postnatal day three (P3). Hindlimb motor recovery and Doppler blood flow perfusion at the site of transection were measured on P10. Immunohistochemistry was used to visualize vessel and neurofilament density for quantification. RESULTS Injection of HIF-activated pericytes resulted in greater vascular density in males but did not result in improved motor function for males or females. Injection of non-HIF-activated pericytes resulted improved motor function recovery in both sexes (males, 2.722 ± 0.31-fold score improvement; females, 3.824 ± 0.58-fold score improvement, P < .05) but produced no significant changes in vessel density. CONCLUSIONS HIF-activated pericytes promote vascular density in males post-SCI. Acute delivery of non-HIF-activated pericytes at the site of injury can improve motor recovery post-SCI.
Collapse
Affiliation(s)
- Jamie N Mayo
- IDEAS 2.0 Centre of Innovation, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.,Division of Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.,Department of Biological Sciences, Idaho State University, Pocatello, ID, USA
| | - Sierra D Kauer
- Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Michele R Brumley
- Department of Psychology, Idaho State University, Pocatello, ID, USA
| | - Shawn E Bearden
- Department of Biological Sciences, Idaho State University, Pocatello, ID, USA
| |
Collapse
|
|
34
|
Abstract
Purpose of review Pericytes are essential components of capillaries in many tissues and organs, contributing to vessel stability and integrity, with additional contributions to microvascular function still being discovered. We review current and foundational studies identifying pericyte differentiation mechanics and their roles in the earliest stages of vessel formation. Recent findings Recent advances in pericyte-focused tools and models have illuminated critical aspects of pericyte biology including their roles in vascular development.Pericytes likely collaborate with endothelial cells undergoing vasculogenesis, initiating direct interactions during sprouting and intussusceptive angiogenesis. Pericytes also provide important regulation of vascular growth including mechanisms underlying vessel pruning, rarefaction, and subsequent regrowth.
Collapse
Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA
| | - Maruf Hoque
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Blacksburg, VA 24061, USA
| | - Clifton Houk
- Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.,Previous Affiliations
| | - Jordan Darden
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Blacksburg, VA 24061, USA.,Previous Affiliations
| | - John C Chappell
- Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA.,Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.,Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061, USA
| |
Collapse
|
|
35
|
Recent developments in regenerative ophthalmology. SCIENCE CHINA-LIFE SCIENCES 2020; 63:1450-1490. [PMID: 32621058 DOI: 10.1007/s11427-019-1684-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/21/2020] [Indexed: 12/13/2022]
Abstract
Regenerative medicine (RM) is one of the most promising disciplines for advancements in modern medicine, and regenerative ophthalmology (RO) is one of the most active fields of regenerative medicine. This review aims to provide an overview of regenerative ophthalmology, including the range of tools and materials being used, and to describe its application in ophthalmologic subspecialties, with the exception of surgical implantation of artificial tissues or organs (e.g., contact lens, artificial cornea, intraocular lens, artificial retina, and bionic eyes) due to space limitations. In addition, current challenges and limitations of regenerative ophthalmology are discussed and future directions are highlighted.
Collapse
|
|
36
|
Kremer H, Gebauer J, Elvers-Hornung S, Uhlig S, Hammes HP, Beltramo E, Steeb L, Harmsen MC, Sticht C, Klueter H, Bieback K, Fiori A. Pro-angiogenic Activity Discriminates Human Adipose-Derived Stromal Cells From Retinal Pericytes: Considerations for Cell-Based Therapy of Diabetic Retinopathy. Front Cell Dev Biol 2020; 8:387. [PMID: 32582693 PMCID: PMC7295949 DOI: 10.3389/fcell.2020.00387] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/29/2020] [Indexed: 12/16/2022] Open
Abstract
Diabetic retinopathy (DR) is a frequent diabetes-associated complication. Pericyte dropout can cause increased vascular permeability and contribute to vascular occlusion. Adipose-derived stromal cells (ASC) have been suggested to replace pericytes and restore microvascular support as potential therapy of DR. In models of DR, ASC not only generated a cytoprotective and reparative environment by the secretion of trophic factors but also engrafted and integrated into the retina in a pericyte-like fashion. The aim of this study was to compare the pro-angiogenic features of human ASC and human retinal microvascular pericytes (HRMVPC) in vitro. The proliferation and the expression of ASC and HRMVPC markers were compared. Adhesion to high glucose-conditioned endothelial extracellular matrix, mimicking the diabetic microenvironment, was measured. The angiogenesis-promoting features of both cell types and their conditioned media on human retinal endothelial cells (EC) were assessed. To identify a molecular basis for the observed differences, gene expression profiling was performed using whole-genome microarrays, and data were validated using PCR arrays and flow cytometry. Based on multiplex cytokine results, functional studies on selected growth factors were performed to assess their role in angiogenic support. Despite a distinct heterogeneity in ASC and HRMVPC cultures with an overlap of expressed markers, ASC differed functionally from HRMVPC. Most importantly, the pro-angiogenic activity was solely featured by ASC, whereas HRMVPC actively suppressed vascular network formation. HRMVPC, in contrast to ASC, showed impaired adhesion and proliferation on the high glucose-conditioned endothelial extracellular matrix. These data were supported by gene expression profiles with differentially expressed genes. The vessel-stabilizing factors were more highly expressed in HRMVPC, and the angiogenesis-promoting factors were more highly expressed in ASC. The vascular endothelial growth factor receptor-2 inhibition efficiently abolished the ASC angiogenic supportive capacities, whereas the addition of angiopoietin-1 and angiopoietin-2 did not alter these effects. Our results clearly show that ASC are pro-angiogenic, whereas HRMVPC are marked by anti-angiogenic/EC-stabilizing features. These data support ASC as pericyte replacement in DR but also suggest a careful risk-to-benefit analysis to take full advantage of the ASC therapeutic features.
Collapse
Affiliation(s)
- Heiner Kremer
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Julian Gebauer
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Susanne Elvers-Hornung
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Stefanie Uhlig
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany.,FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hans-Peter Hammes
- 5th Medical Department, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Elena Beltramo
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Martin C Harmsen
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Carsten Sticht
- Center for Medical Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Harald Klueter
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany.,FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,HEiKA-Heidelberg Karlsruhe Strategic Partnership, Karlsruhe Institute of Technology (KIT), Heidelberg University, Heidelberg, Germany
| | - Agnese Fiori
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Red Cross Blood Donation Service Baden-Württemberg - Hessen, Mannheim, Germany.,HEiKA-Heidelberg Karlsruhe Strategic Partnership, Karlsruhe Institute of Technology (KIT), Heidelberg University, Heidelberg, Germany
| |
Collapse
|
|
37
|
Manavella DD, Cacciottola L, Payen VL, Amorim CA, Donnez J, Dolmans MM. Adipose tissue-derived stem cells boost vascularization in grafted ovarian tissue by growth factor secretion and differentiation into endothelial cell lineages. Mol Hum Reprod 2020; 25:184-193. [PMID: 30824937 DOI: 10.1093/molehr/gaz008] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 01/14/2019] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
Adipose tissue-derived stem cells (ASCs) have multilineage differentiation potential, proangiogenic properties, and the ability to enhance vascularization in xenografted human ovarian tissue. The aim of the present study was to identify the mechanisms behind the proangiogenic effects of ASCs. For this purpose, severe combined immunodeficient (SCID) mice were grafted with frozen-thawed human ovarian tissue. ASCs were labeled by lentiviral transfection for expression of enhanced green fluorescent protein (eGFP), and human ovarian tissue was grafted using a previously described two-step procedure. In the control group, ovarian tissue was transplanted using the standard one-step approach. Samples were collected and analyzed after 7 days. Detection of the eGFP antigen by immunofluorescence showed ASCs surrounding and infiltrating ovarian tissue grafts. Significantly higher vessel density was observed in the ASC group (P = 0.0182 versus control) on Day 7. Co-expression of eGFP, CD34 and CD31 was demonstrated in human vessels, confirming ASC differentiation into human endothelial cell lineages. Increased gene expression of vascular endothelial growth factor (VEGF) was also shown in the ASC group (P = 0.0182 versus control). Immunohistochemistry targeting anti-human VEGF revealed significantly higher expression levels in the ASC group (P = 0.033 versus control), while VEGF and eGFP immunofluorescence showed greater growth factor expression in areas surrounding ASCs. In conclusion, ASCs differentiate into human vessels and promote secretion of VEGF when transplanted together with human ovarian tissue to SCID mouse peritoneum using a two-step ovarian tissue grafting procedure. This is a promising step towards potentially improving ovarian tissue quality and lifespan. Long-term studies should be conducted to investigate ASC safety and efficacy in the context of ovarian tissue transplantation.
Collapse
Affiliation(s)
- D D Manavella
- Pôle de Recherche en Gynécologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. E. Mounier 52, Brussels, Belgium
| | - L Cacciottola
- Pôle de Recherche en Gynécologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. E. Mounier 52, Brussels, Belgium
| | - V L Payen
- Pôle de Recherche en Pédiatrie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. E. Mounier 52, Brussels, Belgium
| | - C A Amorim
- Pôle de Recherche en Gynécologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. E. Mounier 52, Brussels, Belgium
| | - J Donnez
- Society for Research into Infertility, Av. Grandchamp 143, Brussels, Belgium
| | - M M Dolmans
- Pôle de Recherche en Gynécologie, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. E. Mounier 52, Brussels, Belgium.,Service de Gynécologie, Cliniques Universitaires Saint-Luc, Av. Hippocrate 10, Brussels, Belgium
| |
Collapse
|
|
38
|
Restoration of estrous cycles by co-transplantation of mouse ovarian tissue with MSCs. Cell Tissue Res 2020; 381:509-525. [PMID: 32424509 DOI: 10.1007/s00441-020-03204-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 03/12/2020] [Indexed: 12/13/2022]
Abstract
This study investigates the effect of bone marrow (BM-MSCs) and visceral peritoneum (VP-MSCs)-derived mesenchymal stem cells on the transplanted ovary. VP-MSCs and BM-MSCs were obtained from green fluorescent protein-expressing mice (GFP+). Six- to eight-week-old female NMRI mice were divided into four experimental groups, autograft ovarian tissue fragments (AO), autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel (AO-H), autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel containing BM-MSCs (AO-HB) and autograft ovarian tissue fragments encapsulated in fibrin-collagen hydrogel containing VP-MSCs (AO-HP). Intact ovary (IO) was the control group. The estrous cycles resumption time was monitored and at the third estrous cycle, the blood samples and grafted ovaries were evaluated using hormonal, histological and gene expression analysis. Onset of estrous cycles, especially at the second cycle, was earlier in AO-HB and AO-HP groups than in the AO-H group (P < 0.05). Moreover, E2 and FSH levels in AO-HB and AO-HP groups were returned to those of the intact group. However, folliculogenesis was still retarded as compared with the IO group. The gene expression of theca (Lhcgr, Cyp17a1, Gli2, Gli3 and Ptch1), granulosa (Amh and Fshr), oocyte (Zp3 and Gdf9), germ cells (Stella and Prdm1), angiogenesis (VEGF and bFGF) and apoptosis (Bax/Bcl2 and Caspase3) markers was similar in both AO-HB and AO-HP groups. Expression of Amh, Fshr, Gdf9 and VEGF increased only in the AO-HP group whereas expression of Ptch1 increased only in the AO-HB group, as compared with the AO group (P < 0.05). In conclusion, BM-MSCs or VP-MSCs can improve ovarian autotransplantation in mice with no superiority over each other.
Collapse
|
|
39
|
Fiori A, Hammes HP, Bieback K. Adipose-derived mesenchymal stromal cells reverse high glucose-induced reduction of angiogenesis in human retinal microvascular endothelial cells. Cytotherapy 2020; 22:261-275. [PMID: 32247542 DOI: 10.1016/j.jcyt.2020.02.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/12/2020] [Accepted: 02/22/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND AIMS Diabetic retinopathy (DR) is characterized by a progressive alteration of the retinal microvasculature, arising from microaneurysms to leaky vessels and finally abnormal neovascularization. The hyperglycemia-mediated loss of pericytes is a key event in vessel degeneration causing vascular destabilization. To overcome this, mesenchymal stromal cells (MSCs) have been tested as pericyte replacement in several animal models showing repair and regeneration of DR-damaged vasculature. METHODS We hypothesized that adipose-derived mesenchymal stromal cells (ASCs) resist high glucose-induced challenges and protect human retinal microvascular endothelial cells (HRMVECs) from glucose-mediated injury. ASCs and HRMVECs were cultured under normal-glucose (NG; 1 g/L) and high-glucose (HG; 4.5 g/L) conditions comparing their phenotype and angiogenic potential. RESULTS Whereas ASCs were generally unaffected by HG, HG caused a reduction of the angiogenic potential in HRMVEC. Indeed, HG-treated HRMVECs formed fewer vascular tube structures in a basement membrane angiogenesis assay. However, this was not observed in a direct ASC and HRMVEC coculture angiogenesis assay. Increased oxidative stress levels appeared to be linked to the HG-induced reduction of angiogenesis, which could be restored by ASC-conditioned medium and antioxidant treatment. CONCLUSIONS These findings suggest that ASC resist HG-stress whereas endothelial cell angiogenic capacity is reduced. Thus, ASC may be potentially therapeutically active in DR by restoring angiogenic deficits in retinal endothelial cells by the secretion of proangiogenic factors. However, these data also inquire for a thorough risk assessment about the timing of the ASC-based cell therapy, which can be considered advantageous at early stage of DR, but possibly detrimental at the late neo-angiogenic stage of DR.
Collapse
Affiliation(s)
- Agnese Fiori
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Institute Mannheim, Germany
| | - Hans-Peter Hammes
- Endocrinology Department, 5th Medical Department, Medical Faculty Mannheim, Heidelberg University Mannheim, Baden-Württemberg, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Institute Mannheim, Germany; Flow Core Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany.
| |
Collapse
|
|
40
|
Azimi MS, Motherwell JM, Dutreil M, Fishel RL, Nice M, Hodges NA, Bunnell BA, Katz A, Murfee WL. A novel tissue culture model for evaluating the effect of aging on stem cell fate in adult microvascular networks. GeroScience 2020; 42:515-526. [PMID: 32206968 PMCID: PMC7205973 DOI: 10.1007/s11357-020-00178-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 03/04/2020] [Indexed: 12/18/2022] Open
Abstract
In vitro models of angiogenesis are valuable tools for understanding the underlying mechanisms of pathological conditions and for the preclinical evaluation of therapies. Our laboratory developed the rat mesentery culture model as a new tool for investigating mechanistic cell-cell interactions at specific locations across intact blood and lymphatic microvascular networks ex vivo. The objective of this study was to report a method for evaluating the effect of aging on human stem cell differentiation into pericytes during angiogenesis in cultured microvascular networks. DiI labeled exogenous stem cells were seeded onto harvested adult Wistar rat mesenteric tissues and cultured in alpha-MEM + 1% serum for up to 5 days according to four experimental groups: (1) adult human adipose-derived stem cells (hASCs), (2) aged hASCs, (3) adult human bone marrow-derived stem cells (hBMSCs), and (4) aged hBMSCs. Angiogenesis per experimental group was supported by observation of increased vessel density and capillary sprouting. For each tissue per experimental group, a subset of cells was observed in typical pericyte location wrapped along blood vessels. Stem cell differentiation into pericytes was supported by the adoption of elongated pericyte morphology along endothelial cells and positive NG2 labeling. The percentage of cells in pericyte locations was not significantly different across the experimental groups, suggesting that aged mesenchymal stem cells are able to retain their differentiation capacity. Our results showcase an application of the rat mesentery culture model for aging research and the evaluation of stem cell fate within intact microvascular networks.
Collapse
Affiliation(s)
- Mohammad S Azimi
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Jessica M Motherwell
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Maria Dutreil
- Tulane Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Ryan L Fishel
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Matthew Nice
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Nicholas A Hodges
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, 70118, USA
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Bruce A Bunnell
- Tulane Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Adam Katz
- Depart of Surgery, University of Florida School of Medicine, Gainesville, FL, 32611, USA
| | - Walter L Murfee
- J. Crayton Pruitt Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA.
| |
Collapse
|
|
41
|
Bertelli PM, Pedrini E, Guduric-Fuchs J, Peixoto E, Pathak V, Stitt AW, Medina RJ. Vascular Regeneration for Ischemic Retinopathies: Hope from Cell Therapies. Curr Eye Res 2020; 45:372-384. [PMID: 31609636 DOI: 10.1080/02713683.2019.1681004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/11/2019] [Indexed: 12/18/2022]
Abstract
Retinal vascular diseases, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ocular ischemic syndrome and ischemic optic neuropathy, are leading causes of vision impairment and blindness. Whilst drug, laser or surgery-based treatments for the late stage complications of many of these diseases are available, interventions that target the early vasodegenerative stages are lacking. Progressive vasculopathy and ensuing ischemia is an underpinning pathology in many of these diseases, leading to hypoperfusion, hypoxia, and ultimately pathological neovascularization and/or edema in the retina and other ocular tissues, such as the optic nerve and iris. Therefore, repairing the retinal vasculature may prevent progression of ischemic retinopathies into late stage vascular complications. Various cell types have been explored for their vascular repair potential. Endothelial progenitor cells, mesenchymal stem cells and induced pluripotent stem cells are studied for their potential to integrate with the damaged retinal vasculature and limit ischemic injury. Clinical trials for some of these cell types have confirmed safety and feasibility in the treatment of ischemic diseases, including some retinopathies. Another promising avenue is mobilization of endogenous endothelial progenitors, whereby reparative cells are moved from their niche to circulating blood to target and home into ischemic tissues. Several aspects and properties of these cell types have yet to be elucidated. Nevertheless, we foresee that cell therapy, whether through delivery of exogenous or enhancement of endogenous reparative cells, will become a valuable and beneficial treatment for ischemic retinopathies.
Collapse
Affiliation(s)
- Pietro Maria Bertelli
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Edoardo Pedrini
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Jasenka Guduric-Fuchs
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Elisa Peixoto
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Varun Pathak
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Alan W Stitt
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Reinhold J Medina
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| |
Collapse
|
|
42
|
Nwadozi E, Rudnicki M, Haas TL. Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications. Front Cell Dev Biol 2020; 8:77. [PMID: 32117997 PMCID: PMC7033550 DOI: 10.3389/fcell.2020.00077] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
Pericytes are mural vascular cells found predominantly on the abluminal wall of capillaries, where they contribute to the maintenance of capillary structural integrity and vascular permeability. Generally quiescent cells in the adult, pericyte activation and proliferation occur during both physiological and pathological vascular and tissue remodeling. A considerable body of research indicates that pericytes possess attributes of a multipotent adult stem cell, as they are capable of self-renewal as well as commitment and differentiation into multiple lineages. However, pericytes also display phenotypic heterogeneity and recent studies indicate that lineage potential differs between pericyte subpopulations. While numerous microenvironmental cues and cell signaling pathways are known to regulate pericyte functions, the roles that metabolic pathways play in pericyte quiescence, self-renewal or differentiation have been given limited consideration to date. This review will summarize existing data regarding pericyte metabolism and will discuss the coupling of signal pathways to shifts in metabolic pathway preferences that ultimately regulate pericyte quiescence, self-renewal and trans-differentiation. The association between dysregulated metabolic processes and development of pericyte pathologies will be highlighted. Despite ongoing debate regarding pericyte classification and their functional capacity for trans-differentiation in vivo, pericytes are increasingly exploited as a cell therapy tool to promote tissue healing and regeneration. Ultimately, the efficacy of therapeutic approaches hinges on the capacity to effectively control/optimize the fate of the implanted pericytes. Thus, we will identify knowledge gaps that need to be addressed to more effectively harness the opportunity for therapeutic manipulation of pericytes to control pathological outcomes in tissue remodeling.
Collapse
Affiliation(s)
| | | | - Tara L. Haas
- School of Kinesiology and Health Science, Angiogenesis Research Group and Muscle Health Research Centre, York University, Toronto, ON, Canada
| |
Collapse
|
|
43
|
Liu Q, Yang Y, Fan X. Microvascular pericytes in brain-associated vascular disease. Biomed Pharmacother 2020; 121:109633. [DOI: 10.1016/j.biopha.2019.109633] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/31/2019] [Accepted: 11/01/2019] [Indexed: 01/01/2023] Open
|
|
44
|
Caporarello N, D’Angeli F, Cambria MT, Candido S, Giallongo C, Salmeri M, Lombardo C, Longo A, Giurdanella G, Anfuso CD, Lupo G. Pericytes in Microvessels: From "Mural" Function to Brain and Retina Regeneration. Int J Mol Sci 2019; 20:ijms20246351. [PMID: 31861092 PMCID: PMC6940987 DOI: 10.3390/ijms20246351] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/13/2019] [Accepted: 12/14/2019] [Indexed: 12/13/2022] Open
Abstract
Pericytes are branched cells located in the wall of capillary blood vessels that are found throughout the body, embedded within the microvascular basement membrane and wrapping endothelial cells, with which they establish a strong physical contact. Pericytes regulate angiogenesis, vessel stabilization, and contribute to the formation of both the blood-brain and blood-retina barriers by Angiopoietin-1/Tie-2, platelet derived growth factor (PDGF) and transforming growth factor (TGF) signaling pathways, regulating pericyte-endothelial cell communication. Human pericytes that have been cultured for a long period give rise to multilineage progenitor cells and exhibit mesenchymal stem cell (MSC) features. We focused our attention on the roles of pericytes in brain and ocular diseases. In particular, pericyte involvement in brain ischemia, brain tumors, diabetic retinopathy, and uveal melanoma is described. Several molecules, such as adenosine and nitric oxide, are responsible for pericyte shrinkage during ischemia-reperfusion. Anti-inflammatory molecules, such as IL-10, TGFβ, and MHC-II, which are increased in glioblastoma-activated pericytes, are responsible for tumor growth. As regards the eye, pericytes play a role not only in ocular vessel stabilization, but also as a stem cell niche that contributes to regenerative processes in diabetic retinopathy. Moreover, pericytes participate in melanoma cell extravasation and the genetic ablation of the PDGF receptor reduces the number of pericytes and aberrant tumor microvessel formation with important implications for therapy efficacy. Thanks to their MSC features, pericytes could be considered excellent candidates to promote nervous tissue repair and for regenerative medicine.
Collapse
Affiliation(s)
- Nunzia Caporarello
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA;
| | - Floriana D’Angeli
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
| | - Maria Teresa Cambria
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
| | - Saverio Candido
- Section of General and Clinical Pathology and Oncology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy;
| | - Cesarina Giallongo
- Section of Haematology, Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy;
| | - Mario Salmeri
- Section of Microbiology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (M.S.); (C.L.)
| | - Cinzia Lombardo
- Section of Microbiology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (M.S.); (C.L.)
| | - Anna Longo
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
| | - Giovanni Giurdanella
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
| | - Carmelina Daniela Anfuso
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
- Correspondence: (G.L.); (C.D.A.); Tel.: +39-095-4781158 (G.L.); +39-095-4781170 (C.D.A.)
| | - Gabriella Lupo
- Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (F.D.); (M.T.C.); (A.L.); (G.G.)
- Correspondence: (G.L.); (C.D.A.); Tel.: +39-095-4781158 (G.L.); +39-095-4781170 (C.D.A.)
| |
Collapse
|
|
45
|
Huang H, Kolibabka M, Eshwaran R, Chatterjee A, Schlotterer A, Willer H, Bieback K, Hammes HP, Feng Y. Intravitreal injection of mesenchymal stem cells evokes retinal vascular damage in rats. FASEB J 2019; 33:14668-14679. [DOI: 10.1096/fj.201901500r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Hongpeng Huang
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias Kolibabka
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Rachana Eshwaran
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anupriya Chatterjee
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andrea Schlotterer
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hélène Willer
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hans-Peter Hammes
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yuxi Feng
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
46
|
Corliss BA, Ray HC, Patrie JT, Mansour J, Kesting S, Park JH, Rohde G, Yates PA, Janes KA, Peirce SM. CIRCOAST: a statistical hypothesis test for cellular colocalization with network structures. Bioinformatics 2019; 35:506-514. [PMID: 30032263 PMCID: PMC6361237 DOI: 10.1093/bioinformatics/bty638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 07/17/2018] [Indexed: 12/22/2022] Open
Abstract
Motivation Colocalization of structures in biomedical images can lead to insights into biological behaviors. One class of colocalization problems is examining an annular structure (disk-shaped such as a cell, vesicle or molecule) interacting with a network structure (vascular, neuronal, cytoskeletal, organellar). Examining colocalization events across conditions is often complicated by changes in density of both structure types, confounding traditional statistical approaches since colocalization cannot be normalized to the density of both structure types simultaneously. We have developed a technique to measure colocalization independent of structure density and applied it to characterizing intercellular colocation with blood vessel networks. This technique could be used to analyze colocalization of any annular structure with an arbitrarily shaped network structure. Results We present the circular colocalization affinity with network structures test (CIRCOAST), a novel statistical hypothesis test to probe for enriched network colocalization in 2D z-projected multichannel images by using agent-based Monte Carlo modeling and image processing to generate the pseudo-null distribution of random cell placement unique to each image. This hypothesis test was validated by confirming that adipose-derived stem cells (ASCs) exhibit enriched colocalization with endothelial cells forming arborized networks in culture and then applied to show that locally delivered ASCs have enriched colocalization with murine retinal microvasculature in a model of diabetic retinopathy. We demonstrate that the CIRCOAST test provides superior power and type I error rates in characterizing intercellular colocalization compared to generic approaches that are confounded by changes in cell or vessel density. Availability and implementation CIRCOAST source code available at: https://github.com/uva-peirce-cottler-lab/ARCAS. Supplementary information Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Bruce A Corliss
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - H Clifton Ray
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - James T Patrie
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Jennifer Mansour
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - Sam Kesting
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Janice H Park
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - Gustavo Rohde
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Paul A Yates
- Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA
| | - Kevin A Janes
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Shayn M Peirce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| |
Collapse
|
|
47
|
Payne LB, Zhao H, James CC, Darden J, McGuire D, Taylor S, Smyth JW, Chappell JC. The pericyte microenvironment during vascular development. Microcirculation 2019; 26:e12554. [PMID: 31066166 PMCID: PMC6834874 DOI: 10.1111/micc.12554] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/22/2022]
Abstract
Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.
Collapse
Affiliation(s)
- Laura Beth Payne
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
| | - Huaning Zhao
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
| | - Carissa C. James
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Jordan Darden
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - David McGuire
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Graduate Program in Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Sarah Taylor
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
| | - James W. Smyth
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biological Sciences, College of Science, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
| | - John C. Chappell
- Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute, Roanoke, VA 24016, USA
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic State Institute and State University, Blacksburg, VA 24061, USA
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
| |
Collapse
|
|
48
|
Zakirova EY, Valeeva AN, Aimaletdinov AM, Nefedovskaya LV, Akhmetshin RF, Rutland CS, Rizvanov AA. Potential therapeutic application of mesenchymal stem cells in ophthalmology. Exp Eye Res 2019; 189:107863. [PMID: 31669045 DOI: 10.1016/j.exer.2019.107863] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 10/03/2019] [Accepted: 10/23/2019] [Indexed: 01/09/2023]
Abstract
At present a wide variety of methods have been proposed to treat eye disorders, drug therapies are most commonly used. It should be noted that effective treatment modalities especially for degeneration of the retina and optic nerve are lacking. In the last few years stem cell transplantation has been proposed as an alternative method. The opportunities that stem cells provide within clinical use are almost unlimited. These cells are presently applied to treat various traumatic and degenerative disorders due to their unique biologic properties. Stem cells have high proliferative capabilities and are a self-maintained population of cells capable of differentiating into different cell types. Thus, they are represent a very primary stage of a cell lineage. Their ability to differentiate into different pathways provides animals with great plasticity in the renewal of somatic cells in postnatal ontogenesis. Pre-clinical and clinical ophthalmology studies where mesenchymal stem cells are applied and various methods of their administration are discussed herein. In addition the safety and efficacy of using bone marrow- and adipose tissue-derived mesenchymal stem cells have been discussed.
Collapse
Affiliation(s)
| | - A N Valeeva
- Kazan Federal University, Kazan, Russia; Kazan State Medical University, Kazan, Russia
| | | | | | | | | | | |
Collapse
|
|
49
|
Spencer BG, Estevez JJ, Liu E, Craig JE, Finnie JW. Pericytes, inflammation, and diabetic retinopathy. Inflammopharmacology 2019; 28:697-709. [PMID: 31612299 DOI: 10.1007/s10787-019-00647-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus, and a common cause of vision impairment and blindness in these patients, yet many aspects of its pathogenesis remain unresolved. Furthermore, current treatments are not effective in all patients, are only indicated in advanced disease, and are associated with significant adverse effects. This review describes the microvascular features of DR, and how pericyte depletion and low-grade chronic inflammation contribute to the pathogenesis of this common ophthalmic disorder. Existing, novel and investigational pharmacological strategies aimed at modulating the inflammatory component of DR and ameliorating pericyte loss to potentially improve clinical outcomes for patients with diabetic retinopathy, are discussed.
Collapse
Affiliation(s)
- Benjamin G Spencer
- TMOU, Flinders Medical Centre, Southern Adelaide Local Health Network, SA Health, Flinders Drive, Bedford Park, SA, 5042, Australia.
| | - Jose J Estevez
- Flinders Centre for Ophthalmology, Eye and Vision Research, Department of Ophthalmology, Flinders University, Adelaide, Australia
| | - Ebony Liu
- Flinders Centre for Ophthalmology, Eye and Vision Research, Department of Ophthalmology, Flinders University, Adelaide, Australia
| | - Jamie E Craig
- Flinders Centre for Ophthalmology, Eye and Vision Research, Department of Ophthalmology, Flinders University, Adelaide, Australia
| | - John W Finnie
- Discipline of Anatomy and Pathology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| |
Collapse
|
|
50
|
Gaddam S, Periasamy R, Gangaraju R. Adult Stem Cell Therapeutics in Diabetic Retinopathy. Int J Mol Sci 2019; 20:ijms20194876. [PMID: 31575089 PMCID: PMC6801872 DOI: 10.3390/ijms20194876] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/27/2019] [Accepted: 09/29/2019] [Indexed: 12/17/2022] Open
Abstract
Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell therapeutics, have shown variable efficacy in preclinical models due to the multi-faceted nature of the disease. Among the various adult stem cells, mesenchymal stem cells, especially those derived from adipose tissue and bone marrow, have been explored as a possible treatment for DR. This review summarizes the current literature around the various adult stem cell treatments for the disease and outlines the benefits and limitations of the therapeutics that are being explored in the field. The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue. Various methods of mesenchymal stem cell priming to adapt to a hostile retinal microenvironment have been discussed. Current clinical trials and potential safety concerns have been examined, and the future directions of stem cell therapeutics in DR have also been contemplated.
Collapse
Affiliation(s)
- Sriprachodaya Gaddam
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
| | - Ramesh Periasamy
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
| |
Collapse
|