Mesenchymal stem cell transplantation is undergoing extensive evaluation as a cellular therapy in human clinical trials. Because MSCs are easily isolated and amenable to culture expansion in vitro there is a natural desire to test MSCs in many diverse clinical indications. This is exemplified by the rapidly expanding literature base that includes many in vivo animal models. More recently, MSC-derived extracellular vesicles (EVs), which include exosomes and microvesicles (MV), are being examined for their role in MSC-based cellular therapy. These vesicles are involved in cell-to-cell communication, cell signaling, and altering cell or tissue metabolism at short or long distances in the body. The exosomes and MVs can influence tissue responses to injury, infection, and disease. MSC-derived exosomes have a content that includes cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. To the extent that MSC exosomes can be used for cell-free regenerative medicine, much will depend on the quality, reproducibility, and potency of their production, in the same manner that these parameters dictate the development of cell-based MSC therapies. However, the MSC exosome's contents are not static, but rather a product of the MSC tissue origin, its activities and the immediate intercellular neighbors of the MSCs. As such, the exosome content produced by MSCs appears to be altered when MSCs are cultured with tumor cells or in the in vivo tumor microenvironment. Therefore, careful attention to detail in producing MSC exosomes may provide a new therapeutic paradigm for cell-free MSC-based therapies with decreased risk. Stem Cells 2017;35:851-858.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.2575

Concise Review: MSC-Derived Exosomes for Cell-Free Therapy

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

/pdf/applying-extracellular-vesicles-based-therapeutics-in-2o6zkamf5c.pdf

Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper

Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications

Earlier research primarily attributed the effects of mesenchymal stem cell (MSC) therapies to their capacity for local engrafting and differentiating into multiple tissue types. However, recent studies have revealed that implanted cells do not survive for long, and that the benefits of MSC therapy could be due to the vast array of bioactive factors they produce, which play an important role in the regulation of key biologic processes. Secretome derivatives, such as conditioned media or exosomes, may present considerable advantages over cells for manufacturing, storage, handling, product shelf life and their potential as a ready-to-go biologic product. Nevertheless, regulatory requirements for manufacturing and quality control will be necessary to establish the safety and efficacy profile of these products. Among MSCs, human uterine cervical stem cells (hUCESCs) may be a good candidate for obtaining secretome-derived products. hUCESCs are obtained by Pap cervical smear, which is a less invasive and painful method than those used for obtaining other MSCs (for example, from bone marrow or adipose tissue). Moreover, due to easy isolation and a high proliferative rate, it is possible to obtain large amounts of hUCESCs or secretome-derived products for research and clinical use.

https://www.mdpi.com/1422-0067/18/9/1852/pdf

Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine

Here, for the first time, we test a novel hypothesis that systemic treatment of stroke with exosomes derived from multipotent mesenchymal stromal cells (MSCs) promote neurovascular remodeling and functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo) followed by tail vein injection of 100 μg protein from MSC exosome precipitates or an equal volume of vehicle phosphate-buffered saline (PBS) (n=6/group) 24 hours later. Animals were killed at 28 days after stroke and histopathology and immunohistochemistry were employed to identify neurite remodeling, neurogenesis, and angiogenesis. Systemic administration of MSC-generated exosomes significantly improved functional recovery in stroke rats compared with PBS-treated controls. Axonal density and synaptophysin-positive areas were significantly increased along the ischemic boundary zone of the cortex and striatum in MCAo rats treated with exosomes compared with PBS control. Exosome treatment significantly increased the number of newly formed doublecortin (a marker of neuroblasts) and von Willebrand factor (a marker of endothelial cells) cells. Our results suggest that intravenous administration of cell-free MSC-generated exosomes post stroke improves functional recovery and enhances neurite remodeling, neurogenesis, and angiogenesis and represents a novel treatment for stroke.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2013.152

Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats.

Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Exosomes excreted from MSCs can reduce myocardial ischemia/reperfusion damage and protect against acute tubular injury. However, whether MSC-derived exosomes can relieve liver fibrosis and its mechanism remain unknown. Previous work showed that human umbilical cord-MSCs (hucMSCs) transplanted into acutely injured and fibrotic livers could restore liver function and improve liver fibrosis. In this study, it was found that transplantation of exosomes derived from hucMSC (hucMSC-Ex) reduced the surface fibrous capsules and got their textures soft, alleviated hepatic inflammation and collagen deposition in carbon tetrachloride (CCl4)-induced fibrotic liver. hucMSC-Ex also significantly recovered serum aspartate aminotransferase (AST) activity, decreased collagen type I and III, transforming growth factor (TGF)-β1 and phosphorylation Smad2 expression in vivo. In further experiments, we found that epithelial-to-mesenchymal transition (EMT)-associated markers E-cadherin-positive cells increased and N-cadherin- and vimentin-positive cells decreased after hucMSC-Ex transplantation. Furthermore, the human liver cell line HL7702 underwent typical EMT after induction with recombinant human TGF-β1, and then hucMSC-Ex treatment reversed spindle-shaped and EMT-associated markers expression in vitro. Taken together, these results suggest that hucMSC-Ex could ameliorate CCl4-induced liver fibrosis by inhibiting EMT and protecting hepatocytes. This provides a novel approach for the treatment of fibrotic liver disease.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis

In this work, we have reported a vertical CsPbBr3/ZnO heterojunction photodetector for photo-sensing lights from UV to visible band. The ZnO thin film is deposited on the c-sapphire substrate through a molecular beam epitaxy (MBE) technique, and then the CsPbBr3 thin film is synthesized on the as-prepared ZnO film layer by using a solution processing method. The as-prepared CsPbBr3/ZnO heterostructure presents type-II energy band structure induced by the energy band offset effect, which can promote the separation and extraction efficiencies of the photo-generated electron-hole pairs. Compared with the CsPbBr3 based metal-semiconductor-metal (MSM) structure photodetector, the heterojunction photodetector presents higher responsivity and detectivity of 630 µA/W and 7 × 109 Jones. While compared with the ZnO based MSM structure photodetector, the heterojunction device reveals much faster response speeds of 61 µs (rise time) and 1.4 ms (decay time). These findings demonstrate that the CsPbBr3/ZnO heterojunction photodetector is promising for constructing next generation perovskite based optoelectronic devices.

A vertical CsPbBr3/ZnO heterojunction for photo-sensing lights from UV to green band.

Aim: MSC-based therapies have been accepted as a promising approach for treating liver injury. Here we aimed to investigate the effect of hepatocyte growth factor（HGF） modified human umbilical cord MSCs (HGF-hucMSCs) on mouse hepatic injury. Methods: HGF transduction to hucMSCs by using adenovirus-HGF was prepared. HGF-hucMSCs were transplanted into carbon tetrachloride (CCl4)-injured mice. Reverse transcriptase-polymerase chain reaction for the human 17a gene and fluorescence examination of green fluorescent protein positive cell were used to locate exogenous hUCMSCs in mouse livers. For evaluating the recovery of injured liver tissues, the pathological state of the hepatocytes was assessed, and survival rate of the mice was measured. Results: When transplanted into liver injured mouse, hucMSCs could located in the area of liver injury. Pathological examination revealed that the mice in HGF-hucMSCs group showed less inflammation and denaturation than those in GFP-hucMSCs group. Kaplan-Meier survival curves showed that the survival rate in HGF-hucMSCs group was higher than which in GFP-hucMSCs and PBS group. Moreover, the least hepatocyte apoptosis were found in HGF-hucMSCs group. Conclusions: Our results suggest that transplantation of HGF-hucMSCs can accelerate the recovery of mice hepatic injury.

/pdf/hepatocyte-growth-factor-modified-human-umbilical-cord-1v45nqukiu.pdf

Tingfen Li

Papers

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis

A vertical CsPbBr3/ZnO heterojunction for photo-sensing lights from UV to green band.

Hepatocyte growth factor modified human umbilical cord mesenchymal stem cells accelerate the recovery of mouse hepatic injury