Topic Editor RL is a patent inventor on exosome-related patents, PCT/AU2017/050821 and PCT/AU2016/050468. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

This invaluable resource discusses the current revolution in stem cell-based drugs and their potential use in clinical applications. Each chapter is contributed by a pre-eminent scientist in the field. An introductory section presents current stem cell drugs and stem cell-based products and a discussion of production, quality control, mechanisms, and efficacy. Following sections include discussions on stem cell-derived microvesicles based products, and derived exosomes based products. Stem Cell Drugs - A New Generation of Biopharmaceuticals and the other books in the Stem Cells in Clinical Applications series are invaluable to scientists, researchers, advanced students and clinicians working in stem cells, regenerative medicine or tissue engineering. This groundbreaking volume is also essential reading for those researching or studying drug development or pharmaceutical science.

Neural stem cells (NSCs) are located in specific regions of the central nervous system called niches. Those cells are able to self-renew and to differentiate into specialized neuronal cells (neurons, astrocytes and oligodendrocytes). Due to this differentiation property, NSCs are studied to replace neuronal cells and restore neurological functions in patients affected by neurodegenerative diseases. Several therapeutic approaches have been developed and endogenous NSC stimulation is one of the most promising. Currently, there is no active molecule or therapeutic system targeting endogenous CSNs and inducing their differentiation at the same time. The aim of the work was to provide a drug delivery system able both to target endogenous CSNs and to induce their differentiation in situ. Here, we developed and characterized lipidic nanoparticles (LNC) targeting endogenous NSCs. A peptide called NFL-TBS.40-63, known for its affinity towards NSCs, was adsorbed at the surface of LNC. We observed that NFL-LNC specifically targeted NSC from the brain and not from the spinal cord in vitro and in vivo. To explain this specificity, we characterized and compared NFL-LNC interactions with the plasmatic membrane of both cell types. Finally, we demonstrated that by loading retinoic acid in NFL-LNC we were able to induce brain NSC differentiation in vitro and in vivo. This work contributes to the development of efficient and safe therapies for the treatment of neurodegenerative disease via the differentiation of endogenous NSCs.

This book summarizes early pioneering achievements in the field of human neural stem cell (hNSC) research and combines them with the latest advances in stem cell technology, including reprogramming and gene editing. The powerful potential of hNSC to generate and repair the developing and adult CNS has been confirmed by numerous experimental in vitro and in vivo studies. The book presents methods for hNSC derivation and discusses the mechanisms underlying NSC in vitro fate decisions and their in vivo therapeutic mode of action. The long-standing dogma that the human central nervous system (CNS) lacks the ability to regenerate was refuted at the end of the 20th century, when evidence of the presence of neurogenic zones in the adult human brain was found. These neurogenic zones are home to human neural stem cells (hNSCs), which are capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. NSCs isolated from human CNS have a number of clinical advantages, especially the innate potential to differentiate into functional neural cells. Nevertheless, their full clinical exploitation has been hindered by limited access to the tissue and low expansion potential. The search for an alternative to CNS sources of autologous, therapeutically competent hNSCs was the driving force for the many studies proving the in vitro plasticity of different somatic stem cells to generate NSCs and their functional progeny. Now the era of induced pluripotent stem cells has opened entirely new opportunities to achieve research and therapeutic goals with the aid of hNSCs.

Cardiovascular disease (CVD) represents a global medical and economic problem with high morbidity and mortality rates. CVD is often associated with partial occlusion of the blood vessels and tissue ischemia, and restoring blood supply to ischemic tissues is critical to prevent irreversible tissue damage. Therapeutic angiogenesis aims to stimulate the growth of new blood vessels from pre-existing vessels, which offers a valuable tool for treating CVD. Several strategies have been developed to promote angiogenesis, including growth factor delivery and gene therapy. Direct delivery of angiogenic growth factors has the potential to stimulate new blood vessel growth. However, it is limited by short half-lives in vivo, and uncontrolled diffusion of angiogenic factors may also cause undesirable side effects. Gene therapy offers an alternative approach by delivering genes encoding angiogenic factors, but previous approaches often require the use of viral vectors for efficient gene delivery, and are limited by safety concerns such as immunogenicity. The goal of this thesis research is to develop novel strategies for stimulating therapeutic angiogenesis by harnessing stem cells as drug delivery vehicles and to validate the efficacy of non-viral engineered stem cells in vivo using mouse models of hindlimb ischemia. Our strategy takes advantage of the natural homing capacity of stem cells towards ischemic tissues in vivo, and their ability to secrete paracrine signals to stimulate blood vessel growth. Specifically we developed two strategies including: (1) isolating and transfecting stem cells ex vivo using biodegradable polymeric nanoparticles to overexpress therapeutic genes, followed by transplanting non-viral engineered stem cells back to ischemic tissues; and (2) recruiting and programming endogenous stem cells in situ using biomaterials-mediated delivery of biologics. In the first strategy, we have chosen adipose-derived stem cells (ADSCs), an abundantly available autologous cell source that can be easily obtained in a minimally invasive manner. To enhance the paracrine signaling of ADSCs for therapeutic angiogenesis, we transfected ADSCs using in-house developed biodegradable polymeric nanoparticles, which eliminate the dependence on viruses for efficient gene delivery. Using the optimized polymeric vectors, we examined the efficacy of ADSCs overexpressing various angiogenic factors or homing factors on therapeutic angiogenesis in vitro and in vivo. Transplantation of non-viral engineered ADSCs led to significantly enhanced tissue salvage in a murine model of hindlimb ischemia with faster restoration of blood reperfusion and muscle regeneration. Our results suggest that stem cells programmed with biodegradable polymeric nanoparticles can serve as delivery vehicles to express therapeutic factors in situ to promote therapeutic angiogenesis. In the second strategy, we seek to circumvent the need of isolating and manipulating stem cells ex vivo by directly recruiting and transfecting endogenous progenitor cells in situ at the site of ischemia. To achieve this, we developed a biomaterials-mediated delivery platform for sequential release of stem cell homing factors and DNA encoding therapeutic genes. Our results show that biomaterials-mediated release of homing factors followed by delayed DNA delivery enhanced recruitment of endogenous progenitor cells and improved limb salvage in a mouse model of hindlimb ischemia. Finally, we demonstrate the potential of using microfluidic-synthesized microspheres to aid therapeutic angiogenesis using a biomaterials-mediated drug delivery depot.

Mesenchymal stem cell-derived exosomes are at the forefront of research in two of the most high profile and funded scientific areas – cardiovascular research and stem cells. Mesenchymal Stem Cell Derived Exosomes provides insight into the biofunction and molecular mechanisms, practical tools for research, and a look toward the clinical applications of this exciting phenomenon which is emerging as an effective diagnostic. Primarily focused on the cardiovascular applications where there have been the greatest advancements toward the clinic, this is the first compendium for clinical and biomedical researchers who are interested in integrating MSC-derived exosomes as a diagnostic and therapeutic tool. - Introduces the MSC-exosome mediated cell-cell communication - Covers the major functional benefits in current MSC-derived exosome studies - Discusses strategies for the use of MSC-derived exosomes in cardiovascular therapies

Drug Targeting and Stimuli Sensitive Drug Delivery Systems covers recent advances in the area of stimuli sensitive drug delivery systems, providing an up-to-date overview of the physical, chemical, biological and multistimuli-responsive nanosystems. In addition, the book presents an analysis of clinical status for different types of nanoplatforms. Written by an internationally diverse group of researchers, it is an important reference resource for both biomaterials scientists and those working in the pharmaceutical industry who are looking to help create more effective drug delivery systems. Shows how the use of nanomaterials can help target a drug to specific tissues and cells Explores the development of stimuli-responsive drug delivery systems Includes case studies to showcase how stimuli responsive nanosystems are used in a variety of therapies, including camptothecin delivery, diabetes and cancer therapy