Extracellular Vesicle-Associated Proteins in Tissue Repair

The administration of (stem) cell-derived extracellular vesicles (EVs) promotes tissue repair through management of different inflammatory, proliferative and remodeling processes in the body. Despite the widely observed biological and therapeutic roles of EVs in wound healing and tissue repair, knowledge on how EVs activate recipient cells and which EV cargo is responsible for the subsequent functional effects is limited. Recent studies hint toward an important role for proteins as functional EV cargo. Here, we provide an overview of how EV-associated proteins promote tissue repair processes and discuss current challenges in evaluating their contribution to EV function and future directions for translating fundamental insights into clinically relevant EV therapies

Illuminating RNA trafficking and functional delivery by extracellular vesicles

RNA-based therapeutics are highly promising for the treatment of numerous diseases, by their ability to tackle the genetic origin in multiple possible ways. RNA molecules are, however, incapable of crossing cell membranes, hence a safe and efficient delivery vehicle is pivotal. Extracellular vesicles (EVs) are endogenously derived nano-sized particles and possess several characteristics which make them excellent candidates as therapeutic RNA delivery agent. This includes the inherent capability to functionally transfer RNAs in a selective manner and an enhanced safety profile compared to synthetic particles. Nonetheless, the fundamental mechanisms underlying this selective inter- and intracellular trafficking and functional transfer of RNAs by EVs are poorly understood. Improving our understanding of these systems is a key element of working towards an EV-based or EV-mimicking system for the functional delivery of therapeutic RNA. In this review, state-of-the-art approaches to detect and visualize RNA in situ and in live cells are discussed, as well as strategies to assess functional RNA transfer, highlighting their potential in studying EV-RNA trafficking mechanisms

Exosome mimetics: a novel class of drug delivery systems

The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics

The faint stellar halos of massive red galaxies from stacks of more than 42000 SDSS LRG images

We study the properties of massive galaxies at an average redshift of z~0.34 through stacking more than 42000 images of Luminous Red Galaxies from the Sloan Digital Sky Survey. This is the largest dataset ever used for such an analysis and it allows us to explore the outskirts of massive red galaxies at unprecedented physical scales. Our image stacks extend farther than 400 kpc, where the r-band profile surface brightness reaches 30 mag arcsec-2. This analysis confirms that the stellar bodies of luminous red galaxies follow a simple Sersic profile out to 100 kpc. At larger radii the profiles deviate from the best-fit Sersic models and exhibit extra light in the g, r, i and z-band stacks. This excess light can probably be attributed to unresolved intragroup or intracluster light or a change in the light profile itself. We further show that standard analyses of SDSS-depth images typically miss 20% of the total stellar light and underestimate the size of LRGs by 10% compared to our best fit r-band Sersic model of n=5.5 and r_e=13.1 kpc. If the excess light at r>100 kpc is considered to be part of the galaxy, the best fit r-band Sersic parameters are n=5.8 and r_e=13.6 kpc. In addition we study the radially dependent stack ellipticity and find an increase with radius from e=0.25 at r=10 kpc to e=0.3 at r=100 kpc. This provides support that the stellar light that we trace out to at least 100 kpc is physically associated with the galaxies themselves and may confirm that the halos of individual LRGs have higher ellipticities than their central parts. Lastly we show that the broadband color gradients of the stacked images are flat beyond roughly 40 kpc, suggesting that the stellar populations do not vary significantly with radius in the outer parts of massive ellipticals.Comment: Accepted for publication in Ap

Extracellular vesicle heterogeneity and its impact for regenerative medicine applications

Extracellular vesicles (EVs) are cell-derived membrane-enclosed particles that are involved in physiologic and pathologic processes. EVs are increasingly being studied for therapeutic applications in the field of regenerative medicine. Therapeutic application of stem cell-derived EVs has shown great potential to stimulate tissue repair. However, the exact mechanisms through which they induce this effect have not been fully clarified. This may to a large extent be attributed to a lack of knowledge on EV heterogeneity. Recent studies suggest that EVs represent a heterogeneous population of vesicles with distinct functions. The heterogeneity of EVs can be attributed to differences in their biogenesis, and as such, they can be classified into distinct populations that can then be further subcategorized into various subpopulations. A better understanding of EV heterogeneity is crucial for elucidating their mechanisms of action in tissue regeneration. This review provides an overview of the latest insights on EV heterogeneity related to tissue repair, including the different characteristics that contribute to such heterogeneity and the functional differences among EV subtypes. It also sheds light on the challenges that hinder clinical translation of EVs. Additionally, innovative EV isolation techniques for studying EV heterogeneity are discussed. Improved knowledge of active EV subtypes would promote the development of tailored EV therapies and aid researchers in the translation of EV-based therapeutics to the clinic

Challenges and directions in studying cell-cell communication by extracellular vesicles

Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these