Frontiers in Stem Cell and Regenerative Medicine Research

Articular cartilage lesions that may be limited (focal defects) or generalized like in osteoarthritis (OA) constitute a key, unsolved clinical problem as a result of the inadequate ability of this tissue to self-repair. Thus far, none of the pharmacological treatments and surgical options allow to reproduce the original cartilage integrity in patients, resulting instead in the formation of a fibrocartilaginous reparative tissue with poor mechanical function that is unable to withstand natural loading and stresses throughout life. Approaches based on the administration of mesenchymal stem cells (MSCs) provide attractive tools to enhance the repair of cartilage lesions as such cells are easy to acquire, expand, and can specifically commit towards the chondrocyte phenotype. This chapter aims at providing an overview of the most current and innovative strategies based on the implantation of MSCs as a means to enhance cartilage repair both in focal defects and in OA lesions in vivo. These approaches include scaffold-free and scaffold-guided procedures as well as gene-based strategies to stimulate the cell chondrogenic activities as a means to restore the natural structure and mechanical integrity in sites of cartilage damage.

Maternal infections during pregnancy as well as infections post-partum can induce robust alterations in physiological and behavioral functions, resulting in an increased risk for neuropsychiatric disorders later in life. Inflammation also is increasingly recognized as a stimulus that may either positively or negatively regulate the stem cells and progenitors that reside in the brain’s germinal matrices. Metaanalyses have revealed associations between the incidence of premature birth and perinatal inflammation with smaller total brain volumes, cognitive, motor and behavioral deficits in childhood and adolescence. In animal studies where inflammation has been induced during the perinatal period, parallel changes in cognition and behavior have been seen reminiscent of those observed in human clinical studies. Therefore, in this chapter we will review the literature toward the goal of highlighting which inflammatory signals affect the proliferation and differentiation of the stem cells and progenitors of the brain's germinal zones. Other studies show that cytokines produced after CNS inflammation and injury that can similarly affect the endogenous stem cells and progenitors in the nervous system, stimulating or thwarting their attempts to regenerate injured brain cells. Thus, we also will review progress being made in deciphering how the immature cells of the brain’s subventricular and subgranular zones respond to injuries and inflammation-induced cytokines. We will review how flow cytometric analyses have begun to unmask the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations subsequent to brain injuries with a focus on the immature brain. We will discuss how those shifts in neural stem cells and progenitors change in concert with cytokine expression, as a consequence of cytokine exposure and as a function of age.

Cell-based liver therapies are envisaged as a useful therapeutic option to supplement or replace whole organ transplantation by recovering and stabilizing the lost metabolic function for acute and chronic liver diseases. However, success is hampered by the scarce availability of liver tissue to isolate good-quality cells, and by insufficient cell engraftment mainly due to rejection of transplanted cells. Thus new cell sources alternatives to hepatocytes are being considered to obtain more sustained and significant hepatic metabolic correction, and to reduce the waiting-list mortality rate. Human pluripotent stem cells with hepatic differentiation potential represent a valuable cell source for generating large numbers of functional hepatocyte-like cells for liver cell therapy. The immunogenicity and tumorigenicity of these cells are still a bottleneck for successful clinical application. The preclinical proof-of-concept that pluripotent stem cell-derived hepatocytes can improve disease in animal models is being investigated to fully establish efficacy and safety before conducting welldesigned clinical trials. More recent developments in bioengineering and regenerative medicine to augment or replace liver function have extended several complex cellbased approaches to treat liver disease [bioartificial liver devices and bioengineered organs]. Such new strategies offer an alternative to organ transplantation in patients with liver diseases and are currently being rigorously tested and validated in preclinical studies before being safely transferred to the clinical practice.

As the main detoxifying organ of the body, the liver is subject to routine damage. As such it is fitting that the liver has evolved to become a highly regenerative organ. For example, the removal of 2/3 of the liver via partial hepatectomy results in proliferation of hepatocytes in the remaining lobes and recovery of the entire liver in a week. Although it is understood that hepatocytes proliferate after injury, the mechanisms involved are still at debate. One argument is that the liver utilizes progenitor cells, termed “oval cells,” in order to regenerate the damaged tissue after injury. The origin of oval cells is still unclear as certain groups argue they are derived from biliary cells whereas others claim nearly all new hepatocytes are derived from pre-existing hepatocytes with no evidence of progenitor cell contribution. Here, we discuss the current understanding of liver regeneration and a new outlook, which suggests that hepatocytes themselves are plastic and able to dedifferentiate back into their lineage to give rise to new hepatocytes in order to regenerate the liver.

Following a myocardial infarction, the nutrient deprived areas of the heart become ischemic scar tissue. Moreover, the heart can deteriorate further over time, eventually leading to heart failure. The need for strategies for repair/regeneration of heart tissue is undisputed, and many interdisciplinary teams of researchers have examined the roles of signals found in the biochemical, material, mechanical, and electrical niche of the heart in order to direct cardiac cell fate from stem cells and/or develop strategies for the repair and/or replacement of the damaged heart tissue. This chapter will explore the diversity of techniques recently used for: deriving cardiac cells from pluripotent cell sources, organizing and building cardiomyocyte tissue, examining the long-term cell/tissue engraftment, and correlating improvements in cardiac tissue function.

Together with the regenerative medicine (RM) and personalized therapies, nanomedicine represents one of the fields of advanced therapies that are sought to drastically revolutionize heath care and significantly improve quality of life at a global level. Based on nanoscience and nanotechnology, nanomedicine methods have already entered the field of clinical application by means of drug delivery solutions and contrast agents for medical Imagistics while nano-based carrier and nano-biosensors are in different stages of testing for clinical applications. The use of nano-scaled materials, particularly of magnetic nanoparticles (MNPs) has evolved as an increasing field of research in life sciences. Both physical and chemical properties of MNPs are relevant for a wide scale of medical application for the diagnostic, prevention and treatment of various diseases. Iron oxide based MNPs are being explored as agents for cellular magnetic separation magnetic resonance imaging (MRI) or drug delivery. MNPs have been proposed as tracking agents for cell delivery in various cellular therapy scenarios. In the context of multimodal therapies for the treatment of solid malignancies, the use of hyperthermia (HT) as an adjuvant therapy can be traced back to the beginning of the 20th century. During the last decades, different forms of HT have been used in combination with radio- or chemotherapy. However, local and systemic side effects on healthy tissues are limiting its application. MNPs-based HT treatment of malignancies has gained significant interest in the recent years as they are able to deliver local targeted HT of improved precision compared to the traditional methods. MNPs are tested as modalities to increase efficiency of scaffold fabrication, scaffold functionalization and cell patterning in tissue engineering. MNPs bound to cells can be used to deliver highly controllable mechanical stimulation while within a magnetic field, improving stem cell differentiation especially to musculoskeletal lineages. Cells that have incorporated MNPs or magnetic cationic liposomes can be manipulated to construct three dimensional structures for scaffold free tissue engineering strategies such as cell sheet fabrication, spheroid formation or cell clustering. Placed at the frontier between nanomedicine, tissue regeneration and cell therapy, this chapter describes the current applications of MNPs for the design of advanced therapies as well as future avenues for research and development in this increasingly impacting field.