-
The Indian Journal of Medical Research Jul 2019Corneal blindness is one of the major causes of reversible blindness, which can be managed with transplantation of a healthy donor cornea. It is the most successful... (Review)
Review
Corneal blindness is one of the major causes of reversible blindness, which can be managed with transplantation of a healthy donor cornea. It is the most successful organ transplantation in the human body as cornea is devoid of vasculature, minimizing the risk of graft rejection. The first successful transplant was performed by Zirm, and since then, corneal transplantation has seen significant evolution. It has been possible because of the relentless efforts by researchers and the increase in knowledge about corneal anatomy, improvement in instruments and advancements in technology. Keratoplasty has come a long way since the initial surgeries wherein the whole cornea was replaced to the present day where only the selective diseased layer can be replaced. These newer procedures maintain structural integrity and avoid catastrophic complications associated with open globe surgery. Corneal transplantation procedures are broadly classified as full-thickness penetrating keratoplasty and partial lamellar corneal surgeries which include anterior lamellar keratoplasty [sperficial anterior lamellar keratoplasty (SALK), automated lamellar therapeutic keratoplasty (ALTK) and deep anterior lamellar keratoplasty (DALK)] and posterior lamellar keratoplasty [Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK)] broadly.
Topics: Cornea; Corneal Diseases; Corneal Transplantation; Endothelium, Corneal; Graft Rejection; Humans; Keratoplasty, Penetrating; Visual Acuity
PubMed: 31571625
DOI: 10.4103/ijmr.IJMR_141_19 -
Genes & Development Aug 2022Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases....
Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of , , and mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
Topics: Adenocarcinoma of Lung; Animals; Humans; Lung Neoplasms; Mice; Organoids; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Receptor Protein-Tyrosine Kinases
PubMed: 36175034
DOI: 10.1101/gad.349659.122 -
Cells Mar 2020Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed...
Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.
Topics: Adipose Tissue; Animals; Ceramides; Dermatitis, Atopic; Epidermis; Exosomes; Female; Humans; Mesenchymal Stem Cells; Mice
PubMed: 32164386
DOI: 10.3390/cells9030680 -
American Journal of Physiology. Lung... Apr 2022Development of effective treatment strategies for lung tissue destruction as seen in emphysema would greatly benefit from representative human in vitro models of the...
Development of effective treatment strategies for lung tissue destruction as seen in emphysema would greatly benefit from representative human in vitro models of the alveolar compartment. Studying how cellular cross talk and/or (altered) biomechanical cues affect alveolar epithelial function could provide new insight for tissue repair strategies. Preclinical models of the alveolus ideally combine human primary patient-derived lung cells with advanced cell culture applications such as breathing-related stretch, to reliably represent the alveolar microenvironment. To test the feasibility of such a model, we isolated primary alveolar type 2 cells (AEC2s) from patient-derived lung tissues including those from patients with severe emphysema, using magnetic bead-based selection of cells expressing the AEC2 marker HTII-280. We obtained pure alveolar feeder-free organoid cultures using a minimally modified commercial medium. This was confirmed by known AEC2 markers as well as by detection of lamellar bodies using electron microscopy. Following (organoid-based) expansion, cells were seeded on both cell culture inserts and the Chip-S1 Organ-Chip that has a flexible polydimethylsiloxane (PDMS) membrane enabling the application of dynamic stretch. AEC2s cultured for 7 days on inserts or the chip maintained expression of HTII-280, prosurfactant protein C (SP-C), SP-A and SP-B, and zonula occludens-1 (ZO-1) also in the presence of stretch. AEC2s cultured on the chip showed lower expression levels of epithelial-mesenchymal transition-related vimentin expression compared with static cultures on inserts. The combination of a straightforward culture method of patient-derived AEC2s and their application in microfluidic chip cultures supports successful development of more representative human preclinical models of the (diseased) alveolar compartment.
Topics: Alveolar Epithelial Cells; Cells, Cultured; Epithelial Cells; Humans; Lung; Organoids; Pulmonary Alveoli
PubMed: 35137633
DOI: 10.1152/ajplung.00153.2021 -
International Journal of Molecular... Feb 2022Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component,... (Review)
Review
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a two-fold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.
Topics: Animals; Dermatitis, Atopic; Epidermis; Fats; Humans; Inflammation; Lipids
PubMed: 35216234
DOI: 10.3390/ijms23042121 -
Cells Dec 2021The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific... (Review)
Review
The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.
Topics: COVID-19; Humans; Ion Channels; Lamellar Bodies; Lung; Membrane Transport Proteins; Organelles; Pulmonary Alveoli; Pulmonary Surfactants; SARS-CoV-2
PubMed: 35011607
DOI: 10.3390/cells11010045 -
Cells Nov 2022Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic... (Review)
Review
Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
Topics: Humans; Arthrogryposis; Lysosomes; Melanosomes; Rare Diseases; Cholestasis; Kidney Diseases
PubMed: 36429129
DOI: 10.3390/cells11223702 -
Animals : An Open Access Journal From... Jul 2022As an essential component of the skeleton, bone tissue provides solid support for the body and protects vital organs. Bone tissue is a reservoir of calcium, phosphate,... (Review)
Review
As an essential component of the skeleton, bone tissue provides solid support for the body and protects vital organs. Bone tissue is a reservoir of calcium, phosphate, and other ions that can be released or stored in a controlled manner to provide constant concentration in body fluids. Normally, bone development or osteogenesis occurs through two ossification processes (intra-articular and intra-chondral), but the first produces woven bone, which is quickly replaced by stronger lamellar bone. Contrary to commonly held misconceptions, bone is a relatively dynamic organ that undergoes significant turnover compared to other organs in the body. Bone metabolism is a dynamic process that involves simultaneous bone formation and resorption, controlled by numerous factors. Bone metabolism comprises the key actions. Skeletal mass, structure, and quality are accrued and maintained throughout life, and the anabolic and catabolic actions are mostly balanced due to the tight regulation of the activity of osteoblasts and osteoclasts. This activity is also provided by circulating hormones and cytokines. Bone tissue remodeling processes are regulated by various biologically active substances secreted by bone tissue cells, namely RANK, RANKL, MMP-1, MMP-9, or type 1 collagen. Bone-derived factors (BDF) influence bone function and metabolism, and pathophysiological conditions lead to bone dysfunction. This work aims to analyze and evaluate the current literature on various local and systemic factors or immune system interactions that can affect bone metabolism and its impairments.
PubMed: 35953935
DOI: 10.3390/ani12151946