Stem cell therapies and regenerative medicine in China

Stem cells are the core of tissue repair and regeneration,and a promising cell source for novel therapies.In recent years,research into stem cell therapies has been particularly exciting in China.The remarkable advancements in basic stem cell research and clinically effective trials have led to fresh insights into regenerative medicine,such as treatments for sweat gland injury after burns,diabetes,and liver injury.High hopes have inspired numerous experimental and clinical trials.At the same time,government investment and policy support of research continues to increase markedly.However,numerous challenges must be overcome before novel stem cell therapies can achieve meaningful clinical outcomes.     

Stem cell applications for pathologies of the urinary bladder

New stem cell based therapies are undergoing intense research and are widely investigated in clinical fields including the urinary system. The urinary bladder performs critical complex functions that rely on its highly coordinated anatomical composition and multiplex of regulatory mechanisms. Bladder pathologies resulting in severe dysfunction are common clinical encounter and often cause significant impairment of patient’s quality of life. Current surgical and medical interventions to correct urinary dysfunction or to replace an absent or defective bladder are sub-optimal and are associated with notable complications. As a result, stem cell based therapies for the urinary bladder are hoped to offer new venues that could make up for limitations of existing therapies. In this article, we review research efforts that describe the use of different types of stem cells in bladder reconstruction, urinary incontinence and retention disorders. In particular, stress urinary incontinence has been a popular target for stem cell based therapies in reported clinical trials. Furthermore, we discuss the relevance of the cancer stem cell hypothesis to the development of bladder cancer. A key subject that should not be overlooked is the safety and quality of stem cell based therapies introduced to human subjects either in a research or a clinical context.     

Orchestrating stem cell fate: Novel tools for regenerative medicine

Mesenchymal stem cells are undifferentiated cells able to acquire different phenotypes under specific stimuli. In vitro manipulation of these cells is focused on understanding stem cell behavior, proliferation and pluripotency. Latest advances in the field of stem cells concern epigenetics and its role in maintaining self-renewal and differentiation capabilities. Chemical and physical stimuli can modulate cell commitment, acting on gene expression of Oct-4, Sox-2 and Nanog,the main stemness markers, and tissue-lineage specific genes. This activation or repression is related to the activity of chromatin-remodeling factors and epigenetic regulators, new targets of many cell therapies. The aim of this review is to afford a view of the current state of in vitro and in vivo stem cell applications,highlighting the strategies used to influence stem cell commitment for current and future cell therapies. Identifying the molecular mechanisms controlling stem cell fate could open up novel strategies for tissue repairing processes and other clinical applications.     

Stem cell treatments for oropharyngeal dysphagia: Rationale,benefits, and challenges

Dysphagia, defined as difficulty swallowing, is a common symptom negatively impacting millions of adults annually. Estimated prevalence ranges from 14 to 33 percent in those over age 65 to over 70 percent in a nursing home setting. The elderly, those with neurodegenerative diseases, head and neck cancer patients, and those with autoimmune conditions such as Sjögren's syndrome are disproportionately affected. Oropharyngeal dysphagia refers specifically to difficulty in initiating a swallow due to dysfunction at or above the upper esophageal sphincter, and represents a large proportion of dysphagia cases. Current treatments are limited and are often ineffective. Stem cell therapy is a new and novel advancement that may fill a much-needed role in our treatment regimen. Here, we review the current literature regarding stem cell treatments for oropharyngeal dysphagia. Topics discussed include tissue regeneration advancements as a whole and translation of these principles into research surrounding tongue dysfunction, xerostomia, cricopharyngeal dysfunction, and finally an overview of the challenges and future directions for investigation. Although this field of study remains in its early stages, initial promising results show potential for the use of stem cell-based therapies to treat oropharyngeal dysphagia and warrant further research.     

Replication-selective virotherapy for cancer: Biological principles, risk management and future directions.

In the search for novel cancer therapies that can be used in conjunction with existing treatments, one promising area of research is the use of viral vectors and whole viruses. This review describes the underlying biological principles and current status of the field, outlines approaches for improving clinical effectiveness and discusses the unique safety and regulatory issues surrounding viral therapies.     

Targeted gene therapy: frontiers in the development of 'smart drugs'

Chronic diseases, particularly malignancies and immune-mediated inflammatory diseases (IMIDs), are a challenging frontier for clinical diagnosis and treatment, as well as for biomedical research. Current treatment regimens are frequently insufficient and thus new treatment strategies are needed. Novel therapies for disabling such diseases should provide improvements with respect to safety, efficacy and cost. To fulfill these three key criteria, recent research efforts have focused on the development of 'smart drugs'. This review highlights some examples of the rapidly expanding possibilities that current biotechnology has to offer in the development of novel therapeutic strategies for complex diseases such as IMIDs. Special attention is given to advances in, and limitations of, controlled and targeted gene product application in inflammatory diseases.     

Tissue engineering and cell based therapies,from the bench to the clinic: The potential to replace,repair and regenerate

The field of Regenerative Biology as it applies to Regenerative Medicine is an increasingly expanding area of research with hopes of providing therapeutic treatments for diseases and/or injuries that conventional medicines and even new biologic drug therapies cannot effectively treat. Extensive research in the area of Regenerative Medicine is focused on the development of cells, tissues and organs for the purpose of restoring function through transplantation. The general belief is that replacement, repair and restoration of function is best accomplished by cells, tissues or organs that can perform the appropriate physiologic/metabolic duties better than any mechanical device, recombinant protein therapeutic or chemical compound. Several strategies are currently being investigated and include, cell therapies derived from autologous primary cell isolates, cell therapies derived from established cell lines, cell therapies derived from a variety of stem cells, including bone marrow/mesenchymal stem cells, cord blood stem cells, embryonic stem cells, as well as cells tissues and organs from genetically modified animals. This mini-review is not meant to be exhaustive, but aims to highlight clinical applications for the four areas of research listed above and will address a few key advances and a few of the hurdles yet to be overcome as the technology and science improve the likelihood that Regenerative Medicine will become clinically routine.     

Lessons from human teratomas to guide development of safe stem cell therapies

The potential for the formation of teratomas or other neoplasms is a major safety roadblock to clinical application of pluripotent stem cell therapies. Preclinical assessment of the risk of tumor formation in this context poses considerable scientific and regulatory challenges, especially because animal xenograft models may not properly reflect the long-term tumorigenic potential of human cells. A better understanding of the biology of spontaneously occurring teratomas and related tumors in humans can help to guide efforts to assess and minimize the potential hazards of embryonic stem cell or induced pluripotent stem cell therapeutics. Here we review the features of teratomas derived experimentally from human pluripotent stem cells and argue that they most closely resemble spontaneous benign teratomas that occur early in both mouse and human life. The natural history and pathology of these spontaneously occurring teratomas provide important clues for preclinical safety assessment and patient monitoring in trials of stem cell therapies.     

The importance of valid disclosures in the human embryonic stem cell research debate

Abstract.  Misinformation erodes the legitimacy of any public debate. Since the start of human embryonic stem cell research deliberations in the USA, misinformation concerning the nature of human embryos, their availability for research, and the potential for using them to develop new medical therapies have been widespread and persistent. Basic facts, well understood by physicians and biologists, have been so misstated and misrepresented in the news media and political speeches that the general public has been put in a state of constant uncertainty. The solution to the present troubling condition is better education in the form of diligent, honest, and complete scientific disclosure by responsible scientists and physicians; and more care given to accurate reporting by news media. Several key aspects of newly emerging embryonic and non-embryonic stem cell technologies are defined and discussed as they relate to the debate over the use of human embryos for medical research. An important topic for consideration is how to disclose with clarity the scientific basis for human embryonic life. Thereafter, failings in proposed technologies for developing new therapies with human embryonic stem cells, that have been grossly under-reported, are examined. Finally, properties of adult stem cells are presented in contradistinction to embryonic stem cells, both in terms of adult stem cells as a scientifically better alternative to embryonic stem cells and in terms of the technological challenges that must be overcome to realize the potential of adult stem cells for new medical therapies.     

The promise and perils of stem cell therapeutics

Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact.     

Imaging myocardial metabolism

The prevalence of coronary artery disease and heart failure is increasing in modern industrialized countries, fueling the search for novel therapies. Because metabolism and function in the heart are inextricably linked, energy substrate metabolism has provided a potential target for novel therapies and the development of technologies to image myocardial metabolism has been crucial in establishing new therapeutic approaches. Nuclear imaging probes have been used to successfully evaluate aerobic fatty acid metabolism, anaerobic glucose metabolism, and oxidative metabolism and can be used for the accurate, sensitive, and physiological evaluation of therapeutic effects. More recently, with the advent of stem-cell technologies, imaging approaches have been employed to track the fate of stem cells and to monitor the success of these treatments. In the future, our ability to image myocardial metabolism is likely to assist the development of other new therapies to improve the function of the failing heart.     

Basic science review on adipose tissue for clinicians

The recognition that fat contains stem cells has driven further examination into the potential uses of fat and adipose-derived stem cells in a wide number of clinical situations. New information about the harvesting, isolation, and subsequent differentiation properties of isolated adipose-derived stem cells has led to new research into novel tissue-engineered constructs and the transformation of adipose-derived stem cells to induced pluripotent stem cells. Clinically, use of fat grafts and adipose-derived stem cells worldwide and in the United States has dramatically increased in parallel to questions concerning the safety and efficacy of adipose-derived stem cell-based treatments. Currently, the U.S. Food and Drug Administration has not approved the use of isolated adipose-derived stem cells for medical indications.     

Convergence of human pluripotent stem cell,organoid, and genome editing technologies

The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.     

Stem cell therapy in ocular pathologies in the past 20 years

Stem cell therapies are successfully used in various fields of medicine. This new approach of research is also expanding in ophthalmology. Huge investments, resources and important clinical trials have been performed in stem cell research and in potential therapies. In recent years, great strides have been made in genetic research, which permitted and enhanced the differentiation of stem cells. Moreover, the possibility of exploiting stem cells from other districts (such as adipose, dental pulp, bone marrow stem cells, etc.) for the treatment of ophthalmic diseases, renders this topic fascinating. Furthermore, great strides have been made in biomedical engineering, which have proposed new materials and three-dimensional structures useful for cell therapy of the eye. The encouraging results obtained on clinical trials conducted on animals have given a significant boost in the creation of study protocols also in humans. Results are limited to date, but clinical trials continue to evolve. Our attention is centered on the literature reported over the past 20 years, considering animal (the most represented in literature) and human clinical trials, which are limiting. The aim of our review is to present a brief overview of the main types of treatments based on stem cells in the field of ophthalmic pathologies.     

Model systems in stem cell biology

Stem cell scientists and ethicists have focused intently on questions relevant to the developmental stage and developmental capacities of stem cells. Comparably less attention has been paid to an equally important set of questions about the nature of stem cells, their common characteristics, their non-negligible differences and their possible developmental species specificity. Answers to these questions are essential to the project of justly inferring anything about human stem cell biology from studies in non-human model systems--and so to the possibility of eventually developing human therapies based on stem cell biology. After introducing and discussing these questions, I conclude with a brief discussion of the creation of novel model systems in stem cell biology: human-to-animal embryonic chimeras. Such novel model systems may help to overcome obstacles to extrapolation, but they are also scientifically and ethically contentious.     

Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies

Cancer is a primary cause of human fatality and conventional cancer therapies, e.g., chemotherapy, are often associated with adverse side-effects, tumor drug-resistance, and recurrence. Molecularly targeted therapy, composed of small-molecule inhibitors and immunotherapy (e.g., monoclonal antibody and cancer vaccines), is a less harmful alternative being more effective against cancer cells whilst preserving healthy tissues. Drug-resistance, however, caused by negative regulation of cell death signaling pathways, is still a challenge. Circumvention of negative regulators of cell death pathways or development of predictive and response biomarkers is, therefore, quintessential. This review critically discusses the current state of knowledge on targeting negative regulators of cell death signaling pathways including apoptosis, ferroptosis, necroptosis, autophagy, and anoikis and evaluates the recent advances in clinical and preclinical research on biomarkers of negative regulators. It aims to provide a comprehensive platform for designing efficacious polytherapies including novel agents for restoring cell death signaling pathways or targeting alternative resistance pathways to improve the chances for antitumor responses. Overall, it is concluded that nonapoptotic cell death pathways are a potential research arena for drug discovery, development of novel biomarkers and targeted therapies.     

Niche science: The aging stem cell

Studies on stem cell aging are uncovering molecular mechanisms of regenerative decline, providing new insight into potential rejuvenating therapies.Studies on stem cell aging are uncovering molecular mechanisms of regenerative decline, providing new insight into potential rejuvenating therapies. Most human tissues retain an amazing ability to regenerate well into adulthood. Somatic stem cells are central to this ability, replacing damaged cells and thus keeping the body in a highly functional state. Yet this process does not continue unabated forever, as aging is accompanied by a loss of this regenerative capacity. Presently, studies in invertebrate and vertebrate model systems are advancing our understanding of regenerative decline and are identifying strategies for ‘rejuvenating’ therapies that have the potential to extend human health- and lifespan.The feasibility of rejuvenating interventions was demonstrated by classic studies in which exposure to a young systemic environment restored regenerative capacity of muscle stem cells in old mice.¹ Similar rejuvenation has now been demonstrated for the central nervous system, suggesting that such interventions have systemic potential² and raising the question of whether the lifespan of the organism could be extended by restoring the regenerative capacity of adult stem cells. This has already been demonstrated in flies, where improved intestinal stem cell function leads to enhanced longevity.³Such studies have inspired the burgeoning field of “stem cell aging.”^4,5 A recent symposium at the Buck Institute for Research on Aging in Novato, CA showcased the field, bringing together researchers interested in the biology of aging and experts in stem cell biology, and covering topics ranging from basic research in stem cell aging to the use of stem cells in clinical applications. Clear from the meeting is that new molecular insight into stem cell aging is emerging at a rapid pace, revealing both the promises and challenges of deploying stem cell therapies for age-related diseases. The key questions are starting to be answered.