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      Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration

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          Abstract

          Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.

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          Most cited references 224

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          Inflammation in wound repair: molecular and cellular mechanisms.

          In post-natal life the inflammatory response is an inevitable consequence of tissue injury. Experimental studies established the dogma that inflammation is essential to the establishment of cutaneous homeostasis following injury, and in recent years information about specific subsets of inflammatory cell lineages and the cytokine network orchestrating inflammation associated with tissue repair has increased. Recently, this dogma has been challenged, and reports have raised questions on the validity of the essential prerequisite of inflammation for efficient tissue repair. Indeed, in experimental models of repair, inflammation has been shown to delay healing and to result in increased scarring. Furthermore, chronic inflammation, a hallmark of the non-healing wound, predisposes tissue to cancer development. Thus, a more detailed understanding in mechanisms controlling the inflammatory response during repair and how inflammation directs the outcome of the healing process will serve as a significant milestone in the therapy of pathological tissue repair. In this paper, we review cellular and molecular mechanisms controlling inflammation in cutaneous tissue repair and provide a rationale for targeting the inflammatory phase in order to modulate the outcome of the healing response.
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            Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

            Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.
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              • Record: found
              • Abstract: found
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              Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes

              Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) in the brain because of an imbalance between Aβ production and clearance. Neprilysin (NEP) is the most important Aβ-degrading enzyme in the brain. Thus, researchers have explored virus-mediated NEP gene delivery. However, such strategies may entail unexpected risks, and thus exploration of a new possibility for NEP delivery is also required. Here, we show that human adipose tissue-derived mesenchymal stem cells (ADSCs) secrete exosomes carrying enzymatically active NEP. The NEP-specific activity level of 1 μg protein from ADSC-derived exosomes was equivalent to that of ~ 0.3 ng of recombinant human NEP. Of note, ADSC-derived exosomes were transferred into N2a cells, and were suggested to decrease both secreted and intracellular Aβ levels in the N2a cells. Importantly, these characteristics were more pronounced in ADSCs than bone marrow-derived mesenchymal stem cells, suggesting the therapeutic relevance of ADSC-derived exosomes for AD.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                07 May 2020
                May 2020
                : 9
                : 5
                Affiliations
                [1 ]ExoCoBio Exosome Institute (EEI), ExoCoBio Inc., Seoul 08594, Korea; dh.ha@ 123456exocobio.com (D.H.H.); hyunkeun.kim@ 123456exocobio.com (H.-k.K.); junho.lee@ 123456exocobio.com (J.H.L.); sumi.sung@ 123456exocobio.com (S.S.)
                [2 ]School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Korea; purequill@ 123456naver.com
                [3 ]Oaro Dermatology Clinic, Seoul 13620, Korea; banbury@ 123456hanmail.net
                [4 ]Department of Dermatology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwasweong-si, Gyeonggi-do 18450, Korea; jin66666@ 123456hanmail.net
                [5 ]Guam Dermatology Institute, Tamuning, GU 96913, USA; guamderm@ 123456gmail.com
                [6 ]Oaro Dermatology Clinic, Seoul 01695, Korea; jaeyoon007@ 123456hanmail.net
                [7 ]Piena Clinic, Seoul 06120, Korea; hosungeee@ 123456naver.com
                Author notes
                [* ]Correspondence: yongweon.yi@ 123456exocobio.com (Y.W.Y.); ceo@ 123456exocobio.com (B.S.C.); Tel.: +82-2-2038-3915 (B.S.C.)
                [†]

                These authors contributed equally to this article.

                Article
                cells-09-01157
                10.3390/cells9051157
                7290908
                32392899
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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