FIGURE 1 - available via license: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Content may be subject to copyright.
Human and mouse corneal stromal cells demonstrate mesenchymal stromal cells (MSC) features. (A) Bright-field image of passage-4 human corneal MSCs. (B) Flow cytometry analysis demonstrated a homogenous MSC population. More than 95% of the cells were positive for cell surface markers CD73, CD90, CD105, and negative for CD19, CD45, HLA-DR, CD11b, and CD34 (n ¼ 10). (C) Differentiation into the three mesenchymal lineages: I: Osteogenesis: calcium deposition stained with Alizarin Red; II: Adipogenesis: lipid formation stained with LipidTOX; III: Chondrogenesis: Glycosaminoglycans stained with Alcian Blue. (D) Bright-field microscopy image of passage-4 mouse corneal MSCs. (E) Flow cytometry analysis demonstrated a homogenous MSC population. More than 95% of the cells are positive for cell surface markers CD29, Sca-1, CD105, CD44 and CD106 and negative for CD11b, and CD45. (F) Differentiation into the three mesenchymal lineages: I: Calcium deposition stained with Alizarin Red; II: Lipid formation stained with LipidTOX; III: Glycosaminoglycans stained with Alcian Blue.
Source publication
Purpose
To evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC).
Methods
Co-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1−/− mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay...
Contexts in source publication
Context 1
... were successfully isolated from human and mouse corneas and characterized to meet the minimal International Society of Cell Therapy criteria for defining MSCs (Fig. 1). Previous studies have demonstrated that the therapeutic effects of MSCs are largely mediated through their secreted factors. 20,21 We proceeded to test Co-MSC secretome using in vitro assays of angiogenesis. The results indicated that Co-MSC secretome significantly inhibits vascular sprouting and endothelial tube formation compared to ...
Context 2
... For instance, Co-MSCs were shown to have antifibrotic effects and prevent the development of corneal scarring after injury. 1 While majority of studies have shown BM and adipose derived MSCs are proangiogenic, there has been reports that BM-MSCs can block corneal neovascularization. [33][34][35][36][37][38] In partic- ular, MSCs from different sources have been shown to secrete several angiostatic factors, including thrombospondin 1; tissue metalloproteinase inhibitor 1; pentraxin-3 (TSG-14); and PEDF. 37,[39][40][41][42][43][44][45][46][47] In general, the mechanisms that have been proposed for the antiangiogenic effects of MSCs are indirectly based on their anti-inflammatory properties rather than direct antiangiogenic effects. ...
Similar publications
Citations
... Increased macrophage activity, particularly of Cd11c+ macrophages, is one of the precursors to lymphatic vessel appearance in the stroma [73,74]. The prevention of angiogenesis is more direct, with corneal stromal stem cells directly inhibiting vascular endothelial cell sprout formation with anti-angiogenic factors such as sFLT-1 and PEDF [75]. The cornea's avascular nature is vital for maintaining its transparency, and limbal stromal stem cells may in fact contribute to this avascular privilege by orchestrating the prevention of (lymph)angiogenesis, ensuring that new blood vessel formation is physiologically prevented within the cornea. ...
Corneal stromal stem cells (CSSCs) are of particular interest in regenerative ophthalmology, offering a new therapeutic target for corneal injuries and diseases. This review provides a comprehensive examination of CSSCs, exploring their anatomy, functions, and role in maintaining corneal integrity. Molecular markers, wound healing mechanisms, and potential therapeutic applications are discussed. Global corneal blindness, especially in more resource-limited regions, underscores the need for innovative solutions. Challenges posed by corneal defects, emphasizing the urgent need for advanced therapeutic interventions, are discussed. The review places a spotlight on exosome therapy as a potential therapy. CSSC-derived exosomes exhibit significant potential for modulating inflammation, promoting tissue repair, and addressing corneal transparency. Additionally, the rejuvenation potential of CSSCs through epigenetic reprogramming adds to the evolving regenerative landscape. The imperative for clinical trials and human studies to seamlessly integrate these strategies into practice is emphasized. This points towards a future where CSSC-based therapies, particularly leveraging exosomes, play a central role in diversifying ophthalmic regenerative medicine.
... In addition to their multipotentiality for differentiation to various kinds of cells including corneal epithelial cells [14], they have shown the ability to migrate to the site of injury and enhance the process of tissue regeneration [15,16]. Moreover, MSCs can exert their anti-inflammatory and anti-angiogenic properties by secreting different chemokines and growth factors [17,18] such as pigment epithelial-derived factor (PEDF) [19]. Previous studies have also demonstrated that MSCs can inhibit the pro-apoptotic state induced by corneal injury by decreasing expression of Atf4, Bip, and p21 [20]. ...
... These products, mainly growth, anti/proangiogenic and neurotrophic factors, are critical for the correct functioning of the neuroretina and choroid. Among them, the most characterized are VEGF [67,68], 69], PEDF [70], MMPs [71] . These factors could also play a fundamental role in the etiology of several retinal diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and retinopathy of prematurity [86]. ...
Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.
... They have, therefore, shed a new light on treatment of patients suffering from diseases and disorders that do not yet have a definite cure, and have a long history since their discovery to therapy applications [112]. MSCs are present in almost all post-natal/adult organs, i.e., bone marrow [113][114][115], adipose tissue [116,117], dental pulp [118,119], endometrium [120,121], menstrual blood [122,123], peripheral blood [124], salivary gland [125,126], skin and foreskin [127][128][129][130], synovial fluid [131,132], muscle [133][134][135], corneal stroma [136,137], heart [138,139], and lung [140]. Promising sources of MSCs are represented by the extraembryonic/perinatal tissues [141], among which there are the placenta, the chorionic and amniotic membranes [142][143][144], amniotic fluid [145], umbilical cord blood [146], and umbilical cord stroma [147]. ...
Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the “cytokine storm”, that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.
... Moreover, the sub-basal nerve will never fully recover to its original configuration, and current clinical treatment methods to respond to the loss of nerve innervation frequently suffer from low efficacy [7]. To develop more robust and effective treatments for neuro-ophthalmic diseases, researchers have tried many innovative therapies, such as exploiting stem cells and their secreting factors (i.e., EVs), to trigger nerve regeneration in ocular surfaces [8]. In this review article, we discuss innovative approaches and recent developments in isolating, characterizing, and using EVs in experimental and animal models as potentially novel therapeutics for neuro-ophthalmic disorders. ...
Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases.
... Firstly, the source of producer cells for EXO production should be carefully examined because the choice of cells determines the quantity, functional activity, and target clinical application of EXOs. For instance, EXOs derived from corneal stromal stem cells have been shown to be enriched with anti-angiogenic factors, and thus can be used to engineer avascular tissues, such as the cornea [84] , whereas EXOs derived from BMMSCs or AdMSCs have been shown to contain high levels of pro-angiogenic factors that can be used for vascular tissue repair and regeneration [85] . Likewise, MSC-EXOs derived from different tissue sources, including bone marrow, umbilical cord, menstrual blood, and chorion, promote neurite outgrowth in varying degrees [86] . ...
453Three-dimensional bioprinting (3DBP) is an additive manufacturing technique that has emerged as a promising strategy for the fabrication of scaffolds, which can successfully recapitulate the architectural, biochemical, and physical cues of target tissues. More importantly, 3DBP offers fine spatiotemporal control and high submicron scale resolution, which can be leveraged for the incorporation and directional gradient release of single or multiple biomimetic cues, including cell-derived exosomes (EXOs). EXOs are extracellular vesicles that originate from the endosomal compartment of various cell types, with sizes ranging from 30 to120 nm. They act as cell mediators and contain discrete cell constituents, including growth factors, cytokines, lipid moieties, nucleic acids, metabolites, and cell surface markers, depending on the cell type. Essentially, owing to their therapeutic potential, EXOs derived from mesenchymal stem cells (MSCs) have been recently investigated in several clinical trials for the treatment of various conditions, including cancer, diabetes, dry eyes, periodontitis, and acute ischemic stroke. The 3DBP strategy of EXOs is especially useful in tissue engineering and regenerative medicine applications, as tissues can be biofabricated to closely mimic the complex microarchitecture and developmental profiles of native heterogeneous tissues for restoring biological functions. Moreover, EXOs can be manipulated to carry exogenous cargo such as genes or proteins of therapeutic interest, confer multifunctional attributes, and further enhance their tissue regenerative potential. However, significant challenges, including the selection of appropriate bioink, pattern resolution, engineering-defined exosomal gradient, spatial presentation and modulation of EXO release kinetics, as well as EXO stability and storage conditions, must be addressed for the successful translation of therapeutic grade EXOs to clinical settings. In this review, we highlight the recent advances and offer future perspectives on the bioprinting of EXOs as regenerative biotherapeutics for the fabrication of complex heterogeneous tissues that are suitable for clinical transplantation.
... C-MSCs shift macrophages toward an anti-angiogenic phenotype via the secretion of pigment epithelial derived factor (PEDF) [37]. Both PEDF and soluble fms-like tyrosine kinase-1 (sFLT-1) directly inhibit neovascularization [38]. Pirounides et al. found that adipose derived MSCs exhibit the same anti-angiogenic properties when they were administered in a rabbit model of suture induced corneal neovascularization [39]. ...
Introduction:
Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner.
Areas covered:
In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface.
Expert opinion:
Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.
... Finally, conditioned media from limbal fibroblasts have shown promising results [146]. In an LSCD murine model, using limbal-fibroblast-conditioned media resulted in an increase in corneal-epithelial-like cells as well as lower density of conjunctival goblet cells [146]. ...
... Finally, conditioned media from limbal fibroblasts have shown promising results [146]. In an LSCD murine model, using limbal-fibroblast-conditioned media resulted in an increase in corneal-epithelial-like cells as well as lower density of conjunctival goblet cells [146]. ...
... In an animal model of chemical burn, local application of limbal-derived MSCs resulted in an increase in corneal transparency, a decreased epithelial defect, and attenuated corneal neovascularization [158]. Similarly, corneal MSCs secrete high levels of antiangiogenic factors [146]. Although data on the clinical application of MSCs are limited, the first clinical trial using allogeneic human-bone-marrow-derived MSCs reported a success rate of 76.5-85.7%, ...
The corneal epithelium is composed of nonkeratinized stratified squamous cells and has a significant turnover rate. Limbal integrity is vital to maintain the clarity and avascularity of the cornea as well as regeneration of the corneal epithelium. Limbal epithelial stem cells (LESCs) are located in the basal epithelial layer of the limbus and preserve this homeostasis. Proper functioning of LESCs is dependent on a specific microenvironment, known as the limbal stem cell niche (LSCN). This structure is made up of various cells, an extracellular matrix (ECM), and signaling molecules. Different etiologies may damage the LSCN, leading to limbal stem cell deficiency (LSCD), which is characterized by conjunctivalization of the cornea. In this review, we first summarize the basics of the LSCN and then focus on current and emerging bioengineering strategies for LSCN restoration to combat LSCD.
... Inhibition of VEGF function in vivo by sFLT could promote quiescence in confluent endothelial-cell monolayers, act as a feedback mechanism to terminate angiogenesis and vascular permeability, and prevent blood vessel growth into normally avascular tissues, such as cornea and hyaline cartilage. Eslani et al. [11] stated that sFlt-1 is expressed in the eye to maintain avascularity in the cornea. ...
... MSCs induce cellular differentiation leading to promotion of wound healing [51]. Furthermore, MSCs has an attractive powerful ability for self-renewal as well as restricted immunogenicity [46,58], which encourage many researchers to study of the efficacy of MSCs to mini-mise inflammation and reconstruct the transparency of the cornea after its damage [16,44,61]. Bone marrow mesenchymal stem cells (BM-MSCs) greatly ameliorate the injured corneal surface and accelerate its wound healing after alkali burn [42,62]. ...
Background: The X-rays and the visible light are the main source of ultraviolet radiation (UVR). About 90% of ultraviolet B (UVB) is absorbed by the cornea which may promote corneal inflammation, oedema and damage of its epithelial layer. Bone marrow mesenchymal stem cells (BM-MSCs) have been demonstrated to
ameliorate the injured corneal tissue and accelerate its wound healing. This study aimed to compare the healing effect of intravenous (IV) versus subconjunctival (SC) BM-MSCs on the rats’ corneas subjected to UVB-irradiation.
Materials and methods: Ten rats were used as donors for BM-MSCs and the other 40 were allocated into four equal groups: group I (control group), group II (ultraviolet-irradiated group), group III (ultraviolet-irradiated + IV BM-MSCs-treated group) and group IV (ultraviolet-irradiated +SC BM-MSCs-treated group). Rats of all groups were euthanized after 3 weeks and the corneal specimens were processed for histopathological, immunohistochemical and electron microscopy assessment.
Results: Ultraviolet-irradiated group showed remarkable thinning of epithelial thickness, wide partial epithelial separation, and desquamation. Neovascularisation of the disorganised stroma and disrupted Descemet’s membrane were observed. The superficial and basal epithelial cells appeared irregular and separated by wide intercellular spaces and inflammatory cells. Immunohistochemical examination showed a significant decrease in proliferating cell nuclear antigen immunoreaction. In contrast, minimal changes were observed in rats treated with BM-MSCs with more improvement associated with the subconjunctival administration compared to IV route.
Conclusions: Local SC injection of BM-MSCs has an amazing regenerative efficacy on the corneal injury compared to the systemic IV route. (Folia Morphol 2022; 81, 4: 900–916)
