On the Road from Phenotypic Plasticity to Stem Cell Therapy.

In 1981, I published a paper in the first issue of The Journal of Neuroscience with my postdoctoral mentor, Richard Bunge. At that time, the long-standing belief that each neuron expressed only one neurotransmitter, known as Dale's Principle (Dale, 1935), was being hotly debated following a report by French embryologist Nicole Le Douarin showing that neural crest cells destined for one transmitter phenotype could express characteristics of another if transplanted to alternate sites in the developing embryo (Le Douarin, 1980). In the Bunge laboratory, we were able to more directly test the question of phenotypic plasticity in the controlled environment of the tissue culture dish. Thus, in our paper, we grew autonomic catecholaminergic neurons in culture under conditions which promoted the acquisition of cholinergic traits and showed that cells did not abandon their inherited phenotype to adopt a new one but instead were capable of dual transmitter expression. In this Progressions article, I detail the path that led to these findings and how this study impacted the direction I followed for the next 40 years. This is my journey from phenotypic plasticity to the promise of a stem cell therapy.

Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder.

This review presents many but not all the major historical events that have led to our current understanding of gene and stem cell therapies for the treatment of hearing and balance disorders in animal models of these disorders. In order to better understand the application of these emerging therapies to the treatment of inner ear disorders in a clinical setting, it has been necessary to provide some genetic and pathobiology backgrounds from both animal models and clinical disorders. The current focus and goal of gene and stem cell therapies are directed toward understanding the effective treatment of animal models that mimic human disorders of hearing and balance. This approach not only addresses the most effective ways to deliver the gene or stem cell therapies to affected inner ears, it also provides an assessment of the efficacy of the applied therapy(s) in achieving either partial or full restoration of either hearing and/or balance within the animal models receiving these therapeutic interventions. This review also attempts to present a realistic assessment of how close the research fields of gene and stem cell therapies are to application for the treatment of human disorders in a clinical setting. Progress made in developing these novel therapies toward clinical applications would not have been possible without the many pioneering studies and discoveries achieved by the investigators cited in this review. There were also many other excellent studies performed by gifted investigators that were not able to be included within this review. Anat Rec, 303:390-407, 2020. © 2019 American Association for Anatomy.

Regenerative Cardiovascular Therapies: Stem Cells and Beyond.

Although reperfusion therapy has improved outcomes, acute myocardial infarction (AMI) is still associated with both significant mortality and morbidity. Once irreversible myocardial cell death due to ischemia and reperfusion sets in, scarring leads to reduction in left ventricular function and subsequent heart failure. Regenerative cardiovascular medicine experienced a boost in the early 2000s when regenerative effects of bone marrow stem cells in a murine model of AMI were described. Translation from an animal model to stem cell application in a clinical setting was rapid and the first large trials in humans suffering from AMI were conducted. However, high initial hopes were early shattered by inconsistent results of randomized clinical trials in patients suffering from AMI treated with stem cells. Hence, we provide an overview of both basic science and clinical trials carried out in regenerative cardiovascular therapies. Possible pitfalls in specific cell processing techniques and trial design are discussed as these factors influence both basic science and clinical outcomes. We address possible solutions. Alternative mechanisms and explanations for effects seen in both basic science and some clinical trials are discussed here, with special emphasis on paracrine mechanisms via growth factors, exosomes, and microRNAs. Based on these findings, we propose an outlook in which stem cell therapy, or therapeutic effects associated with stem cell therapy, such as paracrine mechanisms, might play an important role in the future. Optimizing stem cell processing and a better understanding of paracrine signaling as well as its effect on cardioprotection and remodeling after AMI might improve not only AMI research, but also our patients' outcomes.

Cell-based therapy for Parkinson's disease: A journey through decades toward the light side of the Force.

This review describes the history, development, and evolution of cell-based replacement therapy for Parkinson's disease (PD), from the first pioneering trials with fetal ventral midbrain progenitors to future trials using stem cells as well as reprogrammed cells. In the spirit of Tom Isaacs, the review takes parallels to the storyline of Star Wars, including the temptations from the dark side and the continuous fight for the light side of the Force. It is subdivided into headings based on the original movies, spanning from A New Hope to the Last Jedi.

Induced Pluripotent Stem Cells: The Most Versatile Source for Stem Cell Therapy.

Cell therapy has existed since the first bone marrow transplant in the 1950s involving identical twins. The blood-forming stem cells were used to restore healthy blood cells for the twin with leukemia. It was not until 1968 that genetic matching (known as human leukocyte antigen matching) was known to be important, and not until 1973 that bone marrow transplants were performed from non-twin-related and nonrelated donors. The most important application of human stem cells is for the generation of cells and tissues for cell-based therapies. Currently, donated organs and tissues are often the only option to replace diseased, injured, or destroyed tissue. The availability for these transplantable tissues and organs is very limited, however. To satisfy the demand for a source for these cells and tissues, induced pluripotent stem cells that have been differentiated into specific cell types can serve as a renewable source of replacement cells and tissues. A bank of suitable human leukocyte antigen-matched cells will be an important source providing immediate availability of cells that are readily scalable, economical, and well characterized. Areas of active pursuit with stem cell therapy is being investigated for treating diseases such as macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, and neurodegenerative diseases. This article describes the advantages and hurdles for the use of induced pluripotent cells as the starting material for a source of replacement cells for regenerative medicine.

Replacing Dopamine Neurons in Parkinson's Disease: How did it happen?

The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.

Induced pluripotent stem cell technology: a decade of progress.

Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field.

Management of Limbal Stem Cell Deficiency: A Historical Perspective, Past, Present, and Future.

PURPOSE: To review the management of limbal stem cell deficiency (LSCD) from a historical perspective, report the current treatment guidelines, and propose potential future treatments. METHODS: A literature review was conducted to identify key publications regarding the management of LSCD since treatments were first reported. The advances in surgical treatments, as well as postoperative management, are described from a historical perspective. In addition, current treatment guidelines, as well as future management strategies, are discussed. RESULTS: The management of LSCD has changed dramatically during the last several decades. Before the understanding of the anatomy and physiology of the limbus, all patients with severe LSCD had a dismal prognosis. It was not until the understanding of the location and function of the limbal stem cells that successful management protocols could be formulated. This research gave rise to medical and surgical treatment that protected or replaced diseased or absent limbal stem cells. Understanding the role of the conjunctiva in severe ocular surface disease was also critical in the management of LSCD. Continued improvement in tissue harvesting and surgical techniques have led to improved outcomes in LSCD patients. CONCLUSION: Significant progress has been made during the last several decades to manage patients with LSCD. A substantial percent of patients can achieve improved visual acuity with current techniques. Continued research with new cell culture and tissue engineering techniques may be the next breakthrough to improve the outcomes for these most challenging patients.

History of fat grafting: from ram fat to stem cells.

Fat injection empirically started 100 years ago to correct contour deformities mainly on the face and breast. The German surgeon Eugene Hollaender (1867-1932) proposed a cocktail of human and ram fat, to avoid reabsorption. Nowadays, fat injection has evolved, and it ranks among the most popular procedures, for it provides the physician with a range of aesthetic and reconstructive clinical applications with regenerative effects on the surrounding tissues. New research from all over the world has demonstrated the role of adipose-derived stem cells, present in the adipose tissue, in the repair of damaged or missing tissues.

Treating Parkinson's disease in the 21st century: can stem cell transplantation compete?

The characteristic and selective degeneration of a unique population of cells-the nigrostriatal dopamine (DA) neurons-that occurs in Parkinson's disease (PD) has made the condition an iconic target for cell replacement therapies. Indeed, transplantation of fetal ventral mesencephalic cells into the DA-deficient striatum was first trialled nearly 30 years ago, at a time when other treatments for the disease were less well developed. Over recent decades standard treatments for PD have advanced, and newer biological therapies are now emerging. In the 21st century, stem cell technology will have to compete alongside other sophisticated treatments, including deep brain stimulation and gene therapies. In this review we examine how stem cell-based transplantation therapies compare with these novel and emerging treatments in the management of this common condition. J. Comp. Neurol. 522:2802-2816, 2014. © 2014 Wiley Periodicals, Inc.

Cardiac stem cell biology: glimpse of the past, present, and future.

Cardiac regeneration strategies and de novo generation of cardiomyocytes have long been significant areas of research interest in cardiovascular medicine. In this review, we outline a variety of common cell sources and methods used to regenerate cardiomyocytes and highlight the important role that key Circulation Research articles have played in this flourishing field.