Current Stem Cell Research & Therapy - Volume 6, Issue 3, 2011

Neurological disorders and injuries are typically chronic and debilitating diseases that frequently lead to the premature death of afflicted individuals, thereby imposing a harsh emotional burden on their family members. These disorders/injuries, which include neurodegenerative diseases (Parkinson and Huntington disease), epilepsy, neuromuscular disorders, spinal cord injury and stroke often pose unique challenges for treatment. Current therapies for CNS related disorders are based on the use of pharmacological agents, which often lead to serious side effects. Therefore there is a great interest in the possibility of repairing the nervous system by transplanting cells that can replace the lost cell populations or, in alternative, induce local neuronal proliferation, differentiation and consequent tissue regeneration. In the last years stem cells, and within them adult stem cells from different sources, have been in the forefront of a new wave of possible therapeutic strategies. In fact different routes have been followed so far. Some strategies are solely based on the transplantation and differentiation potential of different populations of stem cells, others rely on their trophic capability while some recent strategies are purely based on the sole administration of the secretome of stem cells. Other routes have also involved bioengineering approaches, where stem cells are combined with biomaterials, scaffolds and nanotechnology concepts, in order to develop therapies that target the above referred problems. This is in fact an exciting cutting edge field of science, where basic stem cells biology meets state of the art materials science with the common goal of improving the quality of life of afflicted patients. Therefore, I am glad and thankful that a panel of renowned scientists has joined this special issue on “Adult Stem Cells and Tissue Engineering in Central Nervous Regenerative Medicine” and reviewed the most recent data on different topics that may have a strong impact on the future of Central Nervous System Regeneration. I sincerely hope that this special issue contributes to future and important developments within this field. Finally, I would like to thank the editorial staff of Current Stem Cell Research & Therapy at Bentham Science Publishers for their help with the preparation of this special issue.

Current therapies have limited or no capacity to restore lost function, slow ongoing neurodegeneration, or promote regeneration following damage to the brain. Biomaterials are playing an increasingly important role in the development of novel, potentially efficacious approaches to brain treatment and repair. Programmable biomaterials enable and augment the targeted delivery of drugs into the brain and allow cell/tissue transplants to be effectively delivered and integrate into the brain, to serve as delivery vehicles for therapeutic proteins, and rebuild damaged circuits. Similarly, biomaterials are being increasingly used to recapitulate specific aspects of brain niches to promote regeneration and/or repair damaged neuronal pathways with stem cell therapies. Many of these approaches are gaining momentum because nanotechnology allows greater control over material-cell interactions that induce specific developmental processes and cellular responses including differentiation, migration, and outgrowth. This review discusses the state of the art and new directions in the convergence of biomaterial science, drug delivery, and stem cell biology in the treatment of degenerative and malignant brain diseases.

The adult central nervous system (CNS) contains a population of neural stem cells, yet unlike many other tissues, has a very limited capacity for self-repair. Promoting tissue repair and functional recovery following CNS injury or disease is a high priority as there are currently no effective treatments towards this end for the treatment of disorders such as stroke, traumatic brain injury and spinal cord injury. Recent advances in stem cell biology have offered a number of enticing potential avenues and we will discuss these possibilities along with the associated challenges as they pertain to stroke. We will consider exogenous therapies involving the transplantation of adult stem cells, and the mobilization of endogenous stem cells, as well as drug delivery and tissue engineering strategies that enhance and complement the cell based strategies.

Successful repair of the injured brain is critical, as traumatic brain injury pathology often involves a secondary cascade of insults that may ultimately lead to worsened neurologic dysfunction. Damage is balanced by the brain's attempt to repair itself, the genetic profile of the person, underlying health issues, and age, among other factors. The challenge in using a tissue engineering approach to repair and regeneration is centered at the heterogeneous and complex environment, variables that are difficult to measure and interpret. The brain must be in a state that minimizes rejection, inflammation, immune response, and donor cell death to maximize the intended benefit. Tissue engineering, using a bioactive based scaffold to both counter some of the hostile factors and to chaperone donor cells into the brain, has merit, yet the complexity of transplanting a combination biologic construct to the brain has yet to be successfully transferred to the clinic. Several options, such as cell source, scaffold composition, as well as delivery methods will be discussed.

Mesenchymal Stem Cells (MSCs), have been defined and characterized by: 1) their ability to adhere to plastic culture flasks; 2) the positive expression of CD105, CD73, CD90 membrane antigens, and the lack of expression of others (e.g CD45 and CD34) and 3) the ability of differentiation under adequate conditions along the osteogenic, chondrogenic and adipogenic lineages. In recent years, cells with these characteristics have been isolated from the Wharton's jelly of the Umbilical Cord (UC). Similarly to bone marrow MSCs, they have shown multilineage differentiation potential and to be able to provide trophic support to neighboring cells. According to the literature, there are two main populations of cells with a mesenchymal character within the human UC: Wharton's jelly Mesenchymal Stem Cells (WJ-MSCs) and Human Umbilical Cord Perivascular Cells (HUCPVCs). In the present work our aim is to make a comprehensive review on MSC populations of the UC and how these cell populations may be used for future applications in CNS regenerative medicine. Following a brief insight on the general characteristics of MSC like cells, we will discuss the possible sources of stem cells within the WJ and the cord itself (apart UC blood), as well as their phenotypic character. As it has already been shown that these cells hold a strong trophic support to neighbouring cell populations, we will then focus on their secretome, namely which molecules have already been identified within it and their role in phenomena such as immunomodulation. The possible applications of these cell populations to CNS regenerative medicine will be addressed by critically reviewing the work that has been performed so far in this field. Finally, a brief insight will be made on what in the authors' opinion are the major challenges in the field for the future application of these cell populations in CNS regenerative medicine.

Tissue-specific human neural precursor cells (hNPCs) can be isolated from various regions of the developing or adult central nervous system and may serve as a viable source of cells in cell replacement therapies for the treatment of neurodegenerative disorders. However, in order for cell replacement strategies to become a routine therapeutic option for the treatment of neurodegenerative disorders, hNPCs should be generated under standardized and controlled conditions. Studies over the last two decades have focused on developing cell growth media and cell handling protocols for expansion and differentiation of hNPCs in culture. Key studies have reported the development of serum-free growth media and large-scale computer-controlled suspension bioreactors that can support high cell proliferation rates (doubling times < 3 days), multipotentiality, and potential neurogenic differentiation (more than 60% neurons). Moreover, bioengineering studies have focused on controlling culture conditions in suspension bioreactors including inoculation, hydrodynamics of culture, oxygen and nutrients transfer to the cells, monitoring in situ physiological parameters using process control techniques, and expansion for extended periods of time. In addition, in vitro and in vivo characterization of hNPCs have been performed, providing information on stem/progenitor cell characteristics, cell surface analysis, and appropriate type of cells to use in transplantation studies.

The eye is a relatively small but very complex organ. It is responsible for vision. Most of its cells are terminally differentiated, and several pathologies affecting those cells lead to vision loss and eventual blindness. Several years ago, a group of cells, located in the limbus, was identified as having the capacity of self-renewal and later on found to feed the renewal of the corneal epithelial layer. Since then, this niche of stem cells has been studied in order to provide clues that can be valuable for the regeneration of ocular structures. The worldwide shortage of donors, increased risk of transmissible diseases and immune rejection and the increased life expectancy, all contributed for the development of strategies to regenerate or repair ocular tissues. In this review we focus on two approaches for ocular regeneration: one based on stem cells and the other one based on tissue engineering strategies, and present examples where these two strategies overlap. We review the sources of cells and tissue engineering strategies for the regeneration of the cornea and of the retina, summarizing the most relevant and recent findings.

Spinal cord injury (SCI) is a traumatic disorder resulting in a functional deficit that usually leads to severe and permanent paralysis. After the initial insult to the spinal cord, additional structure and function are lost through an active and complex secondary process. Since there is not effective treatment for SCI, several strategies including cellular, pharmacological and rehabilitation therapies have been approached in animal models. Some of them have been proved in clinical trials. In this review we focus on the current state of cell therapies, particularly on cells from adult origin, assayed in preclinical research. Cell types used in SCI therapy include Schwann cells, olfactory ensheathing cells and adult stem cells, such as neural stem cells, umbilical cord blood derived cells, mesenchymal stem cells or induced pluripotent stem cells. There are not yet conclusive evidences on which types of glial or adult stem cells are most effective in SCI treatment. Their ability to incorporate into the damaged spinal cord, to differentiate into neural lineages, to exert neuroprotective effects, to promote regeneration of damaged axons, and to improve functional deficits are still discussed, before translation towards clinical use, as a single therapy or in combination with other strategies.

Neurogenesis in the adult mammalian brain occurs in two specific brain areas, the subventricular zone (SVZ) bordering the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Although these regions are prone to produce new neurons, cultured cells from these neurogenic niches tend to be mixed cultures, containing both neurons and glial cells. Several reports highlight the potential of the self-healing capacity of the brain following injury. Even though much knowledge has been produced on the neurogenesis itself, brain repairing strategies are still far away from patient cure. Here we review general concepts in the neurogenesis field, also addressing the methods available to study neural stem cell differentiation. A major problem faced by research groups and companies dedicated to brain regenerative medicine resides on the lack of good methods to functionally identify neural stem cell differentiation and novel drug targets. To address this issue, we developed a unique single cell calcium imaging-based method to functionally discriminate different cell types derived from SVZ neural stem cell cultures. The unique functional profile of each SVZ cell type was correlated at the single cell level with the immunodetection of specific phenotypic markers. This platform was raised on the basis of the functional response of neurons, oligodendrocytes and immature cells to depolarising agents, to thrombin and to histamine, respectively. We also outline key studies in which our new platform was extremely relevant in the context of drug discovery and development in the area of brain regenerative medicine.