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Histopathology of skin lesions. Parakeratotic hyperkeratosis, intercellular edema, and acanthosis. Hematoxylin and eosin stain. Scale bar = 400 lm (A) and 200 lm (B).
Source publication
Hepatocutaneous syndrome (HS) is an uncommon skin disorder that occurs in conjunction with liver disease and is diagnosed based on decreased plasma concentrations of amino acids and the histopathology of skin lesions. The survival period generally is <6 months. A 10-year-old castrated male Maltese dog was presented for evaluation of lethargy, polyu...
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Background:
Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinop...
Citations
... Veterinary medicine, in particular, has undertaken a significant number of investigations on injecting adipose tissue-derived MSCs [3]. Intravenous injection studies of AdMSCs have been conducted in diverse areas of canine health, encompassing skin diseases, such as hepatocutaneous syndrome [4] and atopic dermatitis [5], digestive disorders like inflammatory bowel disease [6], and musculoskeletal conditions including skeletal muscle injury [7] and semitendinous myopathy [8]. In cats, intravenous infusion studies have been conducted in various areas such as acute/ chronic kidney disease [9][10][11][12][13], feline chronic gingivostomatitis [14,15], asthma [16,17], and enteropathies [18]. ...
Importance:
The intravenous administration of adipose tissue-derived mesenchymal stem cells (AdMSCs) in veterinary medicine is an attractive treatment option. On the other hand, it can result in severe complications, including pulmonary thromboembolism (PTE).
Objective:
The present study assessed the occurrence of PTE after the intravenous infusion of canine AdMSCs (cAdMSCs) into experimental animals.
Methods:
Five-week-old male BALB/c hairless mice were categorized into groups labeled A to G. In the control group (A), fluorescently stained 2 × 106 cAdMSCs were diluted in 200 μL of suspension and injected into the tail vein as a single bolus. The remaining groups included the following: group B with 5 × 106 cells, group C with 3 × 106 cells, group D with 1 × 106 cells, group E with 1 × 106 cells injected twice with a one-day interval, group F with 2 × 106 cells in 100 μL of suspension, and group G with 2 × 106 cells in 300 μL of suspension.
Results:
Group D achieved a 100% survival rate, while none of the subjects in groups B and C survived (p = 0.002). Blood tests revealed a tendency for the D-dimer levels to increase as the cell dose increased (p = 0.006). The platelet count was higher in the low cell concentration groups and lower in the high cell concentration groups (p = 0.028). A histological examination revealed PTE in most deceased subjects (96.30%).
Conclusions and relevance:
PTE was verified, and various variables were identified as potential contributing factors, including the cell dose, injection frequency, and suspension volume.
... The therapy for localized pathologies, such as, for example, osteoarthritis, requires numbers of cells ranging between 2 and 20 × 10 6 cells per joint [38]. In comparison, systemic administrations use variable numbers ranging between 1.5 and 3 × 10 6 cells per kg of animal weight [13,[19][20][21]. These cell dosages indicate the importance of exploring the behavior of cells suspended in administration vehicles using adequate cell numbers to evaluate the role of different storage vehicles effectively. ...
Mesenchymal Stromal Cells (MSCs)-based therapies are rapidly gaining interest in veterinary medicine. Cellular therapy represents a new challenge for practitioners and requires precise coordination between the cell processing laboratory and the veterinary clinic. Cryopreservation is the best method to provide fast, in-time, and long-distance delivery of cells for therapeutic applications. However, potentially toxic cryoprotectants and xenobiotic products make the direct administration of cells impracticable for patients. Alternatively, the cells may be resuspended in a ready-to-use vehicle and shipped to the veterinary clinic. In this study, two nutrient-poor vehicles (physiologic saline and ringer lactate solutions) and two nutrient-rich vehicles (the releasate derived from autologous Platelet Poor Plasma and Platelet Rich Plasma) were tested on adipose tissue-derived canine MSCs (AD-MSCs). AD-MSCs stored for 2, 4, or 24 h in the different media were compared regarding mortality, metabolic activity, and replicative capacity. Furthermore, antioxidant activity and the pattern of expression of genes related to AD-MSCs function were performed following 24 h of storage. The results showed that all the different vehicles preserve cell vitality and replication following short-term storage. In long-term storage, the vehicle and cell density affect cell vitality, proliferation, and gene expression (CCL-2, CXCR-4, and TSG-6). Nutrient-rich vehicles seem better suited to preserve cell functionalities in this contest.
... Os animais afetados, geralmente, apresentam lesões hiperqueratóticas, eritematosas e crostosas em região de coxins plantares (Figura 1), plano nasal, região periorbital (Figura 2) e perianal, junções mucocutâneas (Figura 3) e em pontos de pressão (ALMENDROS; SANDY; KIRBERGER, 2019; BACH; GLASSER, 2013;BYRNE, 1999;DOERR, 2022;MCEWEN, 1994;NAM et al., 2017;OLIVEIRA, 2020;WATSON, 2017); crostas melicéricas e/ou hemorrágicas, espessas e firmemente aderidas em cima de uma base eritematosa, é um achado bastante característico (OLIVEIRA, 2020). As erosões também podem ser vistas em cavidade oral, sendo este um dos motivos da diminuição do apetite (DOERR, 2022). ...
... As erosões também podem ser vistas em cavidade oral, sendo este um dos motivos da diminuição do apetite (DOERR, 2022). As lesões comumente desenvolvem fissuras (WATSON, 2017; OLIVEIRA, 2020) e o animal pode claudicar, devido às lesões dolorosas nos coxins e/ou infecção secundária (DOERR, 2022;NAM et al., 2017;OLIVEIRA, 2020). O paciente também pode apresentar sintomas sistêmicos, tais como letargia, poliúria, polidipsia e inapetência (DOERR, 2022;OLIVEIRA, 2020 A ENM é percebida em, aproximadamente, 70 a 90% dos pacientes humanos diagnosticados com glucagonoma (LI et al., 2022). ...
... O tratamento mais eficaz para a SHC é a administração parenteral de aminoácidos (BACH;GLASSER, 2013;BYRNE, 1999;JAFFEY et al., 2020;LOFTUS et al., 2022;NAM et al., 2017). O tratamento de suporte deve incluir a suplementação com zinco, ácidos graxos ômega-3, bem como analgésicos e antibióticos, caso haja uma infecção secundária (BACH; GLASSER, 2013;DOERR, 2022;JAFFEY et al., 2020;LOFTUS et al., 2022;NAM et al., 2017;WATSON, 2017). ...
A síndrome hepatocutânea (SHC), também conhecida por eritema necrolítico migratório (ENM), necrose epidérmica metabólica (NEM) e ainda dermatite necrolítica superficial (DNS), é uma doença rara, geralmente, relacionada a um tumor hepático ou pancreático, disfunção hepática ou má absorção de nutrientes, devido a algum acometimento gastrointestinal. As lesões dermatológicas características se apresentam hiperqueratóticas, eritematosas e crostosas em região de coxins plantares, plano nasal, região periorbital e perianal, junções mucocutâneas e em pontos de pressão. O diagnóstico se dá por meio de uma abordagem multimodal, que inclui análise bioquímica sérica, mensuração de aminoácidos, alterações hepáticas na ultrassonografia e histopatologia, contribuindo para uma análise mais assertiva. O diagnóstico diferencial deve ser realizado para outras dermatopatias, tais como demodiciose, dermatofitose, foliculite bacteriana, necrólise epidérmica tóxica, lúpus eritematoso sistêmico, pênfigo foliáceo e dermatite por contato. O tratamento é paliativo, valendo-se da administração parenteral de aminoácidos, suplementação com zinco, ácidos graxos ômega-3, bem como analgésicos e antibióticos caso haja uma infecção secundária, no intuito de melhorar a qualidade de vida e aumentar a sobrevida do paciente.
... Allogeneic AD-MSCs were repeatedly injected intravenously or into the hepatic parenchyma. For this condition, the dog's survival with relapsed or limited clinical indications was longer than anticipated [133]. The IV route of delivery seems reasonable for treating hepatic disorders that are sensitive to the MSC treatment in animals because IV injection of MSCs causes the buildup of cells in the liver after they have been removed from the lungs [134]. ...
The introduction of new regenerative therapeutic modalities in the veterinary practice has recently picked up a lot of interest. Stem cells are undifferentiated cells with a high capacity to self-renew and develop into tissue cells with specific roles. Hence, they are an effective therapeutic option to ameliorate the ability of the body to repair and engineer damaged tissues. Currently, based on their facile isolation and culture procedures and the absence of ethical concerns with their use, mesenchymal stem cells (MSCs) are the most promising stem cell type for therapeutic applications. They are becoming more and more well-known in veterinary medicine because of their exceptional immunomodulatory capabilities. However, their implementation on the clinical scale is still challenging. These limitations to their use in diverse affections in different animals drive the advancement of these therapies. In the present article, we discuss the ability of MSCs as a potent therapeutic modality for the engineering of different animals’ tissues including the heart, skin, digestive system (mouth, teeth, gastrointestinal tract, and liver), musculoskeletal system (tendons, ligaments, joints, muscles, and nerves), kidneys, respiratory system, and eyes based on the existing knowledge. Moreover, we highlighted the promises of the implementation of MSCs in clinical use in veterinary practice.
... MSCs therapeutic effect in musculoskeletal ailments like dog, rabbit and horse osteoarthritis/ cartilage defects (Kriston-Pál et al. 2017, Broeckx et al. 2019, Gugjoo et al. 2019, Huňáková et al. 2020, dog bone affections (Tsuzuki et al. 2014, Song et al. 2017, dog periodontal defects (Takewaki et al. 2017), dog and horse muscle/ tendon tears/ injuries (Beerts et al. 2017;Gibson et al. 2017, Taroni et al. 2017, Depuydt et al. 2021) and dog myocardial affections (Pogue et al. 2013, Yang et al. 2021) have been evaluated. Under nonmusculoskeletal tissue ailments, MSCs applications in dog, cattle and horse skin/teat/ corneal/vocal folds injuries/ ulcers , Zubin et al. 2015, Iacono et al. 2016, Iravani et al. 2017, Khashjoori et al. 2019, Mund et al. 2020, dog keratoconjunctivitis sicca (KCS) (Villatoro et al. 2015, Bittencourt et al. 2016, dog spinal cord injuries (SCI) (Escalhão et al. , Bhat et al. 2019, Sharun et al. 2021, dog sciatic nerve injuries (Ding et al. 2010), dog meningoencephalomyelitis of unknown origin (MUO) (Zeira et al. 2015), dog hepatocutaneous syndrome (Nam et al. 2017), dog and cat acute kidney injury (Lee et al. 2017b), dog intervertebral disc diseases (Lee et al. 2009, Sharun et al. 2020, horse reproductive ailments (endometriosis, anestrus, testis) (Grady et al. 2019, Navarrete et al. 2020, de Papa et al. 2020 (Ferrer et al. 2016) and equine laminitis (Marycz et al. 2021). Recently, extended evaluation to canine diabetes, liver affections, tumors, etc have also been started . ...
Stem cell, a wonder cell, acts as a basic unit for an individual development in early prenatal life, and
repairs and regenerates the tissue and/ organ in post-natal life. The stem cell research although conducted extensively is still in its infancy for standardized therapeutics. Among various stem cells types, multi-potential mesenchymal stem cell (MSC) is mainly evaluated for therapeutic applications. These cells have been isolated from almost all the body organs/ tissues and fetal membranes and are culture expanded for higher concentrations. Like human, MSCs harvested from veterinary species are characterized on the basis of International Society for Cellular Therapy (ISCT). Extensive literature on their therapeutic applications in musculoskeletal and non-musculoskeletal systems evidences their potential utility under clinical settings. Currently, limited understanding in their hysiological mechanisms and availability of limited non-uniform in vivo studies restrict their definitive therapeutic applications. Lack of regulatory set up in India makes MSCs research in veterinary medicine a more complicated field. This review details the current status and possible ways to improve MSCs therapeutic applications in veterinary medicine, in general and in Indian system, in particular.
... MSCs can trans-differentiate into the other cell types, including hepatocyte-like cells, islet cell-like cells and neural cell-like cells (Trindade et al. 2017;Mihevc et al. 2020;Nitta et al. 2020). As such, MSCs have also been evaluated in various other dog ailments like diabetes (Zhu et al. 2011;Gautam et al. 2016), meningoencephalomyelitis of unknown origin (MUO) (Zeira et al. 2015), hepatocutaneous syndrome (Nam et al. 2017), liver fibrosis (Matsuda et al. 2017) and acute kidney injury (Lee et al. 2017c). Although very limited to elucidate any significant outcome, all these studies have been demonstrated to be safer and pro to MSCs' therapeutic applications. ...
Stem cells provide novel approaches to improve animal health and productivity and thereby indirectly enrich human life. However, the use of stem cells, including the totipotent single–cell stage embryo, for the generation of genetically modified livestock and refinement of regenerative veterinary medicines has remained a less exploited domain until a few years ago, largely due to the nonavailability of efficient genetic manipulation tools. The inception of sequence-targeted genetic manipulation tools based on bacterial adaptive defense system, clustered regularly interspaced short palindromic repeat (CRISPR), and CRISPR-associated (Cas) protein (CRISPR/Cas) has enabled the bioengineers to harness the stem cell for the animal and human benefits in the way never done before. CRISPR/Cas-based genetic manipulation tools, due to its simplicity, high sequence specificity, and muliplexibility features, has dramatically broadened the dimension of stem cell applications in both the animal and human world, ranging from stem cell-based patient-specific therapeutics and anticancer vaccine development to the generation of genetically modified large animals with improved traits of agricultural and biomedical importance. This chapter provides an overview of various CRISPR/Cas-based gene editing and regulation tools that have been instrumented for genomic modulation of mammalian cells to date. It discusses the critical elements of a typical CRISPR/Cas-based genetic manipulation experiment for efficient modulation of mammalian cells. Based on the reported studies, this chapter sheds light on CRISPR/Cas tools’ potency to advance and accelerate the stem cell uses to benefit veterinary research.
... MSCs can trans-differentiate into the other cell types, including hepatocyte-like cells, islet cell-like cells and neural cell-like cells (Trindade et al. 2017;Mihevc et al. 2020;Nitta et al. 2020). As such, MSCs have also been evaluated in various other dog ailments like diabetes (Zhu et al. 2011;Gautam et al. 2016), meningoencephalomyelitis of unknown origin (MUO) (Zeira et al. 2015), hepatocutaneous syndrome (Nam et al. 2017), liver fibrosis (Matsuda et al. 2017) and acute kidney injury (Lee et al. 2017c). Although very limited to elucidate any significant outcome, all these studies have been demonstrated to be safer and pro to MSCs' therapeutic applications. ...
Mammary gland (MG) biology has attracted researchers’ attention in every mammalian species. Apart from the natural curiosity to understand the mammalian biology wherein newborns are nourished by milk, the incidence of benign and metastatic breast tumor further instigated the scientific community to understand the detailed cellular and molecular events so that the diagnosis, treatment, and prevention could be implemented. The mouse MG has served as the closest MG model to understand the anatomy and physiology despite several differences in the endocrine and reproductive systems of mice and humans. In bovine, the very immediate interest has been to improve milk production from dairy animals. Globally, the average milk yield from dairy animals has so far remained forwardly progressive. Nevertheless, disease like mastitis and the existence of low milk-yielding cows in population have necessitated accelerated research on understanding bovine mammary gland biology, host–pathogen relationship, cyclic changes in molecular and cellular physiology during puberty, pregnancy, lactation, and involution. Proteomics deals with studying many proteins together, thus deriving comprehensive information on cellular physiology. Along with antibodies, the application of mass spectrometry in the study of proteins has revolutionized the investigation method as never before. The complexity in tissue architecture of MG comprises many cell types, and their continuous turnover in the lifetime of an animal constantly challenged our mind and approach to discern cell identity correctly. It will not have been possible without the knowledge of cell type-specific marker proteins, which again owes a lot to proteomics. This chapter selectively discusses the application of mass spectrometry-based proteomics for mammary epithelial cells and mammary stem cells in MG in the context of cell-specific biomarkers, functional differentiation, and diseases.
... Most reported outcomes for dogs with HCS are poor (ie, average survival of 3-6 months from time of diagnosis), 3,9 despite sporadic reports of survival times >2 years. [11][12][13] Superior outcomes for dogs with HCS classically are thought to be achieved by administering IV amino acid (IV-AA) solutions. 4 In conjunction with IV-AA infusions, high protein diets, traditionally commercial diets supplemented with whey protein, have been a mainstay of treatment for dogs with HCS. 4 More recently, combined administration of IV lipid with IV-AA infusions was reported to manage HCS in a single dog for 24 months. ...
Background
Superficial necrolytic dermatitis (SND) in dogs is a rare disorder most commonly associated with hepatocutaneous syndrome. Although often reported as fatal, sporadically reported long‐term remissions might be more common than previously believed and linked to treatment regimens.
Hypothesis/Objectives
Evaluate treatments and associated outcomes in dogs with hepatocutaneous‐associated hepatopathy (HCH) with or without SND, designated collectively aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES).
Animals
Forty‐one dogs of various breeds and ages diagnosed with ACHES.
Methods
Retrospective study. Electronic surveys, medical records (2014‐2019), and communication with veterinarians provided data. Three treatment categories were each dichotomized: IV amino acid (IV‐AA) infusions (≥2 vs <2), supplements including S‐adenosylmethionine (SAMe), arginine with ornithine, glutathione, lysine, proline, omega‐3 fatty acids, or zinc (≥3 vs <3), and diet type (home‐cooked vs commercial). Optimal treatment was defined as receiving ≥2 IV‐AA treatments, ≥3 nutritional supplements, and a home‐cooked diet.
Results
Most dogs (29/41, 71%) received IV‐AA infusions (23/29, ≥2 infusions). Twenty‐one dogs (51%) were fed commercial diets; 17/41 (41%) were fed home‐cooked diets. Most dogs received SAMe (32/41, 78%) and a median of 3 supplements. In 4 dogs, HCH remission occurred. Overall all‐cause median survival time (MST) was 359 days, and disease‐specific MST was 557 days (range, 1‐1783 days). Optimally treated dogs (n = 9) lived significantly longer (MST, >1783 days, P = .02) than variably treated dogs (MST, 214 days).
Conclusions and Clinical Importance
Optimized ACHES management can resolve SND and HCH and confer long‐term survival.
... Over the past decade, the use of mesenchymal stem cell (MSC) treatments in dogs has been investigated as an interesting and innovative alternative to current conventional therapies. Promising results were described for a variety of conditions such as osteoarthritis, tendon and ligament lesions, liver diseases, atopic dermatitis and inflammatory bowel disease [1][2][3][4][5][6][7][8]. The most frequently used sources of canine MSCs are autologous or allogeneic adipose tissue-derived MSCs. ...
... A significant difference between the free 99m Tc and radiolabelled ePB-MSCs relating to the AUC (P-value = 0.003) for ID% in the liver was seen for study 1. These findings support the potential use of intravenously administered ePB-MSCs for the treatment of liver diseases such as acute liver injuries or hepatocutaneous syndrome [6,8]. ...
Background
Mesenchymal stem cell treatments in dogs have been investigated as a potential innovative alternative to current conventional therapies for a variety of conditions. So far, the precise mode of action of the MSCs has yet to be determined. The aim of this study was to gain more insights into the pharmacokinetics of MSCs by evaluating their biodistribution in healthy dogs after different injection routes.
Methods
Three different studies were performed in healthy dogs to evaluate the biodistribution pattern of radiolabelled equine peripheral blood-derived mesenchymal stem cells following intravenous, intramuscular and subcutaneous administration in comparison with free 99m Technetium. The labelling of the equine peripheral blood-derived mesenchymal stem cells was performed using stannous chloride as a reducing agent. Whole-body scans were obtained using a gamma camera during a 24-h follow-up.
Results
The labelling efficiency ranged between 59.58 and 83.82%. Free 99m Technetium accumulation was predominantly observed in the stomach, thyroid, bladder and salivary glands, while following intravenous injection, the 99m Technetium-labelled equine peripheral blood-derived mesenchymal stem cells majorly accumulated in the liver throughout the follow-up period. After intramuscular and subcutaneous injection, the injected dose percentage remained very high at the injection site.
Conclusions
A distinct difference was noted in the biodistribution pattern of the radiolabelled equine peripheral blood-derived mesenchymal stem cells compared to free 99m Technetium indicating equine peripheral blood-derived mesenchymal stem cells have a specific pharmacokinetic pattern after systemic administration in healthy dogs. Furthermore, the biodistribution pattern of the used xenogeneic equine peripheral blood-derived mesenchymal stem cells appeared to be different from previously reported experiments using different sources of mesenchymal stem cells.
... Over the past decade the use of mesenchymal stem cell (MSC) treatments in dogs has been investigated as an interesting and innovative alternative to current conventional therapies. Promising results were described for a variety of conditions such as osteoarthritis, tendon and ligament lesions, liver diseases, atopic dermatitis and in ammatory bowel disease [1,2,3,4,5,6,7,8]. The most frequently used sources of canine MSCs are autologous or allogeneic adipose tissue derived MSCs. ...
... study 1 and study 3) of the ePB-MSCs which remained stable during the rst 6 hours following the injection and only decreased slightly 24 hours post injection [15]. These ndings support the potential use of intravenously administered ePB-MSCs for the treatment of liver diseases such as acute liver injuries or hepatocutaneous syndrome [6,8]. ...
Background: Mesenchymal stem cell treatments in dogs have been investigated as a potential innovative alternative to current conventional therapies for a variety of conditions. So far, the precise mode of action of the MSCs has yet to be determined. The aim of this study was to gain more insights in the pharmacokinetics of MSCs by evaluating their biodistribution in healthy dogs after different injection routes.
Methods: Three different studies were performed in healthy dogs to evaluate the biodistribution of radiolabelled equine peripheral blood-derived mesenchymal stem cells following intravenous, intramuscular and subcutaneous administration in comparison with free 99mTechnetium. The labelling of the equine peripheral blood-derived mesenchymal stem cells was performed using stannous chloride as reducing agent. Whole body scans were obtained using a gamma camera during a 24h follow-up.
Results: The labelling efficiency ranged between 59.58 and 83.82%. Free 99mTechnetium accumulation was predominantly observed in stomach, thyroid, bladder and salivary glands while, following intravenous injection, the 99mTechnetium labelled equine peripheral blood-derived mesenchymal stem cells majorly accumulated in the liver throughout the follow-up period. After intramuscular and subcutaneous injection, the injected dose percentage remained very high at the injection site.
Conclusions: A distinct difference was noted in biodistribution of the radiolabelled equine peripheral blood-derived mesenchymal stem cells compared to free 99mTechnetium indicating equine peripheral blood-derived mesenchymal stem cells have a specific pharmacokinetic pattern after systemic administration in healthy dogs. Furthermore, the natural biodistribution pattern of the used equine peripheral blood-derived mesenchymal stem cells appeared to be different to previously reported experiments using different sources of mesenchymal stem cells.
