Stem Cell-based Treatments Research Articles

Stem Cells for Temporomandibular Joint Repair and Regeneration.

Temporomandibular Disorders (TMD) represent a heterogeneous group of musculoskeletal and neuromuscular conditions involving the temporomandibular joint (TMJ), masticatory muscles and/or associated structures. They are a major cause of non-dental orofacial pain. As a group, they are often multi-factorial in nature and have no common etiology or biological explanations. TMD can be broadly divided into masticatory muscle and TMJ disorders. TMJ disorders are characterized by intra-articular positional and/or structural abnormalities. The most common type of TMJ disorders involves displacement of the TMJ articular disc that precedes progressive degenerative changes of the joint leading to osteoarthritis (OA). In the past decade, progress made in the development of stem cell-based therapies and tissue engineering have provided alternative methods to attenuate the disease symptoms and even replace the diseased tissue in the treatment of TMJ disorders. Resident mesenchymal stem cells (MSCs) have been isolated from the synovia of TMJ, suggesting an important role in the repair and regeneration of TMJ. The seminal discovery of pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have provided promising cell sources for drug discovery, transplantation as well as for tissue engineering of TMJ condylar cartilage and disc. This review discusses the most recent advances in development of stem cell-based treatments for TMJ disorders through innovative approaches of cell-based therapeutics, tissue engineering and drug discovery.

Stem cell based therapies for age-related macular degeneration: The promises and the challenges.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV-AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed.

Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review.

The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies, which aim to improve ease of use and cost-effectiveness, are progressively explored. The use of MSCs in cartilage repair makes it possible to develop single-stage cell-based therapies. However, true single-stage procedures rely on one intervention, which will limit cell sources to fraction concentrates containing autologous MSCs or culture-expanded allogeneic MSCs. So far, it seems both autologous and allogeneic cells can safely be applied, but clinical studies are still ongoing and little information on clinical outcome is available. Further development of cell-based therapies may lead to clinical-grade, standardized, off-the-shelf products with easy handling for orthopedic surgeons. Although as of yet no preclinical or clinical studies are ongoing which explore the use of induced pluripotent stem cells for cartilage repair, a good manufacturing practice-grade induced pluripotent stem cell line might become the basis for such a product in the future, providing that cell fate can be controlled. The use of stem cells in clinical trials brings along new ethical issues, such as proper controls and selecting primary outcome measures. More clinical trials are needed to estimate detailed risk-benefit ratios and trials must be carefully designed to minimize risks and burdens for patients while choosing outcome measures that allow for adequate comparison with results from similar trials. In this review, we discuss the different aspects of new stem cell-based treatments, including safety and ethical issues, as well as provide an overview of current clinical trials exploring these approaches and future perspectives.

Stem Cell-Based Therapy in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a progressive fibrosing disorder for which there is no cure and no pharmacological treatment capable of increasing in a meaningful way the survival rate. Lung transplantation remains the only possible treatment for patients with advanced disease, although the increase in 5-year survival is only 45 %. Some preclinical studies have generated promising results about the therapeutic potential of exogenous stem cells. However, two initial clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or unrelated-donor, placenta-derived mesenchymal stem cells have not convincingly demonstrated that these treatments are acceptably safe. The results of other ongoing clinical trials may help to identify the best source and delivery route of mesenchymal stem cells and to estimate the risk of unwanted effects related to the mesenchymal nature of the transplanted cells. Considering that most of the therapeutic potential of these cells has been ascribed to paracrine signaling, the use of mesenchymal stem cell-derived secretome as an alternative to the transplantation of single cell suspension may circumvent many regulatory and clinical problems. Technical and safety concerns still limit the possibility of clinical applications of other promising interventions that are based on the use of human amnion stem cells, embryonic stem cells or induced pluripotent stem cells to replace or regenerate the dysfunctional alveolar epithelium. We summarize the current status of the field and identify major challenges and opportunities for the possible future integration of stem cell-based treatments into the currently recommended clinical management strategy for idiopathic pulmonary fibrosis.

Human neural stem cell-derived cultures in three-dimensional substrates form spontaneously functional neuronal networks.

Differentiated human neural stem cells were cultured in an inert three-dimensional (3D) scaffold and, unlike two-dimensional (2D) but otherwise comparable monolayer cultures, formed spontaneously active, functional neuronal networks that responded reproducibly and predictably to conventional pharmacological treatments to reveal functional, glutamatergic synapses. Immunocytochemical and electron microscopy analysis revealed a neuronal and glial population, where markers of neuronal maturity were observed in the former. Oligonucleotide microarray analysis revealed substantial differences in gene expression conferred by culturing in a 3D vs a 2D environment. Notable and numerous differences were seen in genes coding for neuronal function, the extracellular matrix and cytoskeleton. In addition to producing functional networks, differentiated human neural stem cells grown in inert scaffolds offer several significant advantages over conventional 2D monolayers. These advantages include cost savings and improved physiological relevance, which make them better suited for use in the pharmacological and toxicological assays required for development of stem cell-based treatments and the reduction of animal use in medical research. Copyright © 2015 John Wiley & Sons, Ltd.

Current Progress in Stem Cell-Based Gene Therapy for Articular Cartilage Repair

Administration of mesenchymal stem cells (MSCs) that have a reliable potential for chondrogenic differentiation is a promising approach currently employed to treat articular cartilage lesions (focal defects and osteoarthritis) in patients as a mean to enhance the poor intrinsic capabilities of this specialized tissue for self-repair. However, there is still a critical need for improved designs, as reproduction of a native structural and functional unit in sites of cartilage damage is not occurring upon implantation of such cells. With the availability of optimized gene transfer systems, gene therapy offers powerful tools to stimulate the chondrogenic process in MSCs via the effective, safe, and durable delivery of candidate sequences with chondroprotective and/or chondroregenerative properties, both in vitro and in experimental models of cartilage lesions in vivo. In the present article, we provide an overview of the current advances in gene- and stem cell-based treatments employed to promote cartilage repair in focal defects and for osteoarthritis, and discuss the challenges that remain to be addressed for a safe translation of such procedures into the clinics.

Stem cell-based treatments against stroke: observations from human proof-of-concept studies and considerations regarding clinical applicability.

Ischemic stroke remains a heavy burden for industrialized countries. The only causal therapy is the recanalization of occluded vessels via thrombolysis, which due to a narrow time window still can be offered only to a minority of patients. Since the majority of patients continues to exhibit neurological deficits even following successful thrombolysis, restorative therapies are urgently needed that promote brain remodeling and repair once stroke injury has occurred. Due to their unique properties of action, stem cell-based strategies gained increasing interest during recent years. Using various stroke models in both rodents and primates, the transplantation of stem cells, namely of bone marrow derived mesenchymal stem cells (MSCs) or neural progenitor cells (NPCs), has been shown to promote neurological recovery most likely via indirect bystander actions. In view of promising observations, clinical proof-of-concept studies are currently under way, in which effects of stem and precursor cells are evaluated in human stroke patients. In this review we summarize already published studies, which due to the broad experience in other medical contexts mostly employed bone marrow-derived MSCs by means of intravenous transplantation. With the overall number of clinical trials limited in number, only a fraction of these studies used non-treated control groups, and only single studies were adequately blinded. Despite these limitations, first promising results justify the need for more elaborate clinical trials in order to make stem cell transplantation a success for stroke treatment in the future.

The Rho kinase inhibitor Y-27632 facilitates the differentiation of bone marrow mesenchymal stem cells.

The selective in vitro expansion and differentiation of multipotent stem cells are critical steps in cell-based regenerative therapies, but technical challenges have limited cell yield and thus the success of these potential treatments. The Rho GTPases and downstream Rho kinases (Rho coiled-coil kinases or ROCKs) are central regulators of cytoskeletal dynamics during the cell cycle and thus help determine the balance between stem cells self-renewal, lineage commitment, and apoptosis. Here, we examined if suppression of ROCK signaling enhances the efficacy of bone marrow-derived mesenchymal stem cells (BMSCs) differentiation into neurons and neuroglial cells. BMSCs were cultured in epidermal growth factor (EGF, 10µg/l) and basic fibroblastic growth factor (bFGF, 10µg/l) in the presence or absence of the Rho kinase inhibitor Y-27632 (10µM). The expression levels of neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence and Western blotting. The average number of NSE-positive cells increased from 83.20±8.677 (positive ratio 0.2140±0.0119) to 109.20±8.430 (positive ratio 0.3193±0.0161) per visual field in the presence of Y-27632, while GFAP-positive cell number increased from 96.30±8.486 (positive ratio 0.18±0.0152) to 107.50±8.683 (positive ratio 0.27±0.0115) (P<0.05 for both). Both NSE and GFAP protein expression levels were enhanced significantly by Y-27632 treatment (NSE: 0.74±0.05 vs. 1.03±0.06; GFAP: 0.64±0.08 vs. 0.97±0.05, both P<0.01) as indicated by Western blots. The Rho kinase inhibitor Y-27632 concomitant with EGF and bFGF stimulation promotes BMSC differentiation into neural cells. Control of Rho kinase activity may enhance the efficiency of stem cell-based treatments for neurodegenerative diseases.

Developing neural stem cell-based treatments for neurodegenerative diseases.

Owing to the aging of the population, our society now faces an impending wave of age-related neurodegenerative pathologies, the most significant of which is Alzheimer’s disease. Currently, no effective therapies for Alzheimer’s disease have been developed. However, recent advances in the fields of neural stem cells and human induced pluripotent stem cells now provide us with the first real hope for a cure. The recent discovery by Blurton-Jones and colleagues that neural stem cells can effectively deliver disease-modifying therapeutic proteins throughout the brains of our best rodent models of Alzheimer’s disease, combined with recent advances in human nuclear reprogramming, stem cell research, and highly customized genetic engineering, may represent a potentially revolutionary personalized cellular therapeutic approach capable of effectively curing, ameliorating, and/or slowing the progression of Alzheimer’s disease.

Promising new treatment targets in patients with fibrosing lung disorders.

The processes of lung fibrogenesis and fibrotic healing are common to a number of conditions with different etiologies. The lungs are the only affected organ in some cases, whereas in others, several organ systems are involved. Therapeutic options can be discussed from various perspectives. In this review, we address the localization of therapeutic targets with regard to cell compartments, including secreted ligands, cell surface, plasma membrane-cytosol interplay, cytosol and nucleus. Complex approach using stem cell therapy is also discussed. As the prognosis of patients with these disorders remains grim, treatment combinations targeting different molecules within the cell should sometimes be considered. It is reasonable to assume that blocking specific pathways will more likely lead to disease stabilization, while stem cell-based treatments could potentially restore lung architecture. Gene therapy could be a candidate for preventive care in families with proven specific gene polymorphisms and documented familial lung fibrosis. Chronobiology, that takes into account effect of circadian rhythm on cell biology, has demonstrated that timed drug administration can improve treatment outcomes. However, the specific recommendations for optimal approaches are still under debate. A multifaceted approach to interstitial lung disorders, including cooperation between those doing basic research and clinical doctors as well as tailoring research and treatment strategies toward (until now) unmet medical needs, could improve our understanding of the diseases and, above all, provide benefits for our patients.

Mesenchymal stem cell-based therapy in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Multiple sclerosis (MS) is a common neurodegenerative disease that presents after an auto-reactive immune response against constituents of the central nervous system. Demyelination, inflammation, and white matter lesions are all hallmarks of this disease. Clinical research supports the use of mesenchymal stem cells (MSCs) as therapy for MS to ameliorate symptoms and pathology. MSCs can be isolated from multiple tissues, including adipose and bone marrow, and are able to migrate to sites of pathology, release anti-inflammatory factors, and provide immunomodulatory and neuroprotective effects once administered. Numerous studies have demonstrated the beneficial effects of MSCs in experimental autoimmune encephalomyelitis (EAE), an induced model of MS. EAE can be induced in several species; however, the mouse is commonly used for therapeutic testing. In the following chapter, scientists will be able to learn how to prepare reagents and MSCs (e.g., isolate, culture, and expand) as well as skillfully execute induction of EAE in mice and administer stem cell-based treatments. Standard methods used to evaluate the disease progression and analyze postmortem tissues are also included.

Differentiation of pluripotent stem cells into retinal pigmented epithelium.

Ocular diseases affect millions worldwide and dramatically influence the quality of life. Although much is known about ocular biology and disease pathologies, effective treatments are still lacking. The eye is well suited for application of emerging cell-based therapies. This chapter explores the development of stem cell-based treatments for age-related macular degeneration (AMD), a prevalent ocular disease in the elderly. Retinal pigmented epithelium (RPE), a cell type implicated in AMD, has been derived from both induced pluripotent stem cells and embryonic stem cells (ESC). Rapidly advancing research has generated various methods of RPE differentiation and several transplantation strategies. Clinical trials are already underway using suspensions of ESC-derived RPE and others are soon to follow. This chapter will provide an overview of current derivation and transplantation strategies for stem cell-derived RPE for the treatment of AMD and other related ocular diseases.

The Global Landscape of Stem Cell Clinical Trials

To provide a comprehensive analysis of clinical trials (CTs) listed in worldwide registries involving new applications for stem cell-based treatments and account for the role of industry. We developed a data set of 4749 stem cell CTs up to 2013 in worldwide registries. We defined 1058 novel CTs (i.e., trials that were not observational in nature; did not involve an established stem cell therapy for an established indication, such as hematopoietic stem cells for leukemia; and did not investigate supportive measures). Based on trial descriptions, we manually coded these for eight additional elements. Our analysis details the characteristics of novel stem cell CTs (e.g., stem cell types being tested, disease being targeted, and whether interventions were autologous or allogeneic), geotemporal trends, and private sector involvement as sponsor or collaborator. The field is progressing at a steady pace with emerging business models for stem cell therapeutics. However, therapeutic rhetoric must be tempered to reflect current clinical and research realities.

Adult Human Nasal Mesenchymal-Like Stem Cells Restore Cochlear Spiral Ganglion Neurons After Experimental Lesion

A loss of sensory hair cells or spiral ganglion neurons from the inner ear causes deafness, affecting millions of people. Currently, there is no effective therapy to repair the inner ear sensory structures in humans. Cochlear implantation can restore input, but only if auditory neurons remain intact. Efforts to develop stem cell-based treatments for deafness have demonstrated progress, most notably utilizing embryonic-derived cells. In an effort to bypass limitations of embryonic or induced pluripotent stem cells that may impede the translation to clinical applications, we sought to utilize an alternative cell source. Here, we show that adult human mesenchymal-like stem cells (MSCs) obtained from nasal tissue can repair spiral ganglion loss in experimentally lesioned cochlear cultures from neonatal rats. Stem cells engraft into gentamicin-lesioned organotypic cultures and orchestrate the restoration of the spiral ganglion neuronal population, involving both direct neuronal differentiation and secondary effects on endogenous cells. As a physiologic assay, nasal MSC-derived cells engrafted into lesioned spiral ganglia demonstrate responses to infrared laser stimulus that are consistent with those typical of excitable cells. The addition of a pharmacologic activator of the canonical Wnt/β-catenin pathway concurrent with stem cell treatment promoted robust neuronal differentiation. The availability of an effective adult autologous cell source for inner ear tissue repair should contribute to efforts to translate cell-based strategies to the clinic.

Use of “MGE Enhancers” for Labeling and Selection of Embryonic Stem Cell-Derived Medial Ganglionic Eminence (MGE) Progenitors and Neurons

The medial ganglionic eminence (MGE) is an embryonic forebrain structure that generates the majority of cortical interneurons. MGE transplantation into specific regions of the postnatal central nervous system modifies circuit function and improves deficits in mouse models of epilepsy, Parkinson's disease, pain, and phencyclidine-induced cognitive deficits. Herein, we describe approaches to generate MGE-like progenitor cells from mouse embryonic stem (ES) cells. Using a modified embryoid body method, we provided gene expression evidence that mouse ES-derived Lhx6+ cells closely resemble immature interneurons generated from authentic MGE-derived Lhx6+ cells. We hypothesized that enhancers that are active in the mouse MGE would be useful tools in detecting when ES cells differentiate into MGE cells. Here we demonstrate the utility of enhancer elements [422 (DlxI12b), Lhx6, 692, 1056, and 1538] as tools to mark MGE-like cells in ES cell differentiation experiments. We found that enhancers DlxI12b, 692, and 1538 are active in Lhx6-GFP+ cells, while enhancer 1056 is active in Olig2+ cells. These data demonstrate unique techniques to follow and purify MGE-like derivatives from ES cells, including GABAergic cortical interneurons and oligodendrocytes, for use in stem cell-based therapeutic assays and treatments.

Differences Between Parkinson’s and Huntington’s Diseases and Their Role for Prioritization of Stem Cell-Based Treatments

The problems of allocation of scarce resources and priority setting in health care have so far not been much studied in the context of stem cell-based therapeutic applications. If and when competitive cost effective stem cell-based therapies are available, the problem of priority setting - to whom should stem cellbased therapies be offered and on what grounds - is discussed in this article using the examples of Parkinson's Disease (PD) and Huntington's Disease (HD). The aim of this paper is to examine the presently known differences between PD and HD and analyze the role of these differences for setting priorities of stem cell-based therapeutic applications to treat these diseases. To achieve this aim, we (1) present the theoretical framework used in the analysis; (2) compare PD and HD in terms of health related and non-health related consequences of these diseases for patients, their relatives and third parties; (3) analyze the ethical relevance of observed differences for priority setting given different values and variables; (4) compare PD and HD in terms of social justice related consequences of stem cell-based therapies; and (5) analyze the ethical relevance of these differences for priority setting given different values and variables. We argue that the steps of analysis applied in this paper could be helpful when setting priorities among treatments of other diseases with similar differences as those between PD and HD.

Chinese Newspaper Coverage of (Unproven) Stem Cell Therapies and their Providers

China is a primary destination for stem cell tourism, the phenomenon whereby patients travel abroad to receive unproven stem cell-based treatments that have not been approved in their home countries. Yet, much remains unknown about the state of the stem cell treatment industry in China and about how the Chinese view treatments and providers. Given the media's crucial role in science/health communication and in framing public dialogue, this study sought to examine Chinese newspaper portrayal and perceptions of stem cell treatments and their providers. Based on a content analysis of over 300 newspaper articles, the study revealed that while Chinese newspaper reporting is generally neutral in tone, it is also inaccurate, overly positive, heavily influenced by "interested" treatment providers and focused on the therapeutic uses of stem cells to address the health needs of the local population. The study findings suggest a need to counterbalance providers' influence on media reporting through strategies that encourage media uptake of accurate information about stem cell research and treatments.

Stem cell-based therapies for osteoarthritis

Regenerative medicine offers the exciting potential of developing alternatives to total joint replacement for treating osteoarthritis. In this article, we highlight recent work that addresses key challenges of stem cell-based therapies for osteoarthritis and provide examples of innovative ways in which stem cells can aid in the treatment of osteoarthritis. Significant progress has been made in understanding the challenges to successful stem cell therapy, such as the effects of age or disease on stem cell properties, altered stem cell function due to an inflammatory joint environment and phenotypic instability in vivo. Novel scaffold designs have been shown to enhance the mechanical properties of tissue-engineered cartilage and have also improved the integration of newly formed tissue within the joint. Emerging strategies such as injecting stem cells directly into the joint, manipulating endogenous stem cells to enhance regenerative capacity and utilizing stem cells for drug discovery have expanded the potential uses of stem cells in treating osteoarthritis. Several recent studies have greatly advanced the development and preclinical evaluation of potential stem cell-based treatments for osteoarthritis through novel approaches focused on cell therapy, tissue engineering and drug discovery.

Applications of stem cells in interdisciplinary dentistry and beyond: An overview

In medicine stem cell–based treatments are being used in conditions like Parkinson's disease, neural degeneration following brain injury, cardiovascular diseases, diabetes, and autoimmune diseases. In dentistry, recent exciting discoveries have isolated dental stem cells from the pulp of the deciduous and permanent teeth, from the periodontal ligament, and an associated healthy tooth structure, to cure a number of diseases. The aim of the study was to review the applications of stem cells in various fields of dentistry, with emphasis on its banking, and to understand how dental stem cells can be used for regeneration of oral and non-oral tissues conversely. A Medline search was done including the international literature published between 1989 and 2011. It was restricted to English language articles and published work of past researchers including in vitro and in vivo studies. Google search on dental stem cell banking was also done. Our understanding of mesenchymal stem cells (MSC) in the tissue engineering of systemic, dental, oral, and craniofacial structures has advanced tremendously. Dental professionals have the opportunity to make their patients aware of these new sources of stem cells that can be stored for future use, as new therapies are developed for a range of diseases and injuries. Recent findings and scientific research articles support the use of MSC autologously within teeth and other accessible tissue harvested from oral cavity without immunorejection. A future development of the application of stem cells in interdisciplinary dentistry requires a comprehensive research program.

Glycoengineering of HCELL, the Human Bone Marrow Homing Receptor: Sweetly Programming Cell Migration

The successful clinical implementation of adoptive cell therapeutics, including bone marrow transplantation and other stem cell-based treatments, depends critically on the ability to deliver cells to sites where they are needed. E-selectin, an endothelial C-type lectin, binds sialofucosylated carbohydrate determinants on its pertinent ligands. This molecule is expressed in a constitutive manner on bone marrow and dermal microvascular endothelium, and inducibly on post-capillary venules at all sites of tissue injury. Engagement of E-selectin with relevant ligand(s) expressed on circulating cells mediates initial "tethering/rolling" endothelial adhesive interactions prerequisite for extravasation of blood-borne cells at any target tissue. Most mammalian cells express high levels of a transmembrane glycoprotein known as CD44. A specialized glycoform of CD44 called "Hematopoietic Cell E-/L-selectin Ligand" (HCELL) is a potent E-selectin ligand expressed on human cells. Under native conditions, HCELL expression is restricted to human hematopoietic stem/progenitor cells. We have developed a technology called "Glycosyltransferase-Programmed Stereosubstitution" (GPS) for custom-modifying CD44 glycans to create HCELL on the surface of living cells. GPS-based glycoengineering of HCELL endows cell migration to endothelial beds expressing E-selectin. Enforced HCELL expression targets human mesenchymal stem cell homing to marrow, licensing transendothelial migration without chemokine signaling via a VLA-4/VCAM-1-dependent "Step 2-bypass pathway." This review presents an historical framework of the homing receptor concept, and will describe the discovery of HCELL, its function as the bone marrow homing receptor, and how enforced expression of this molecule via chemical engineering of CD44 glycans could enable stem cell-based regenerative medicine and other adoptive cell therapeutics.