Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell-based therapies. However, the efficacy and underlying mechanisms of EV-based treatment in hepatic ischemia-reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC-EVs (huc-MSC-EVs) could protect against IRI-induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc-MSC-EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress-induced cell death in vitro. Interestingly, we found that the mitochondria-located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc-MSC-EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc-MSCs decreased the level of MnSOD in huc-MSC-EVs and attenuated the antiapoptotic and antioxidant capacities of huc-MSC-EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc-MSC-EVs on hepatic IRI and evaluate their preclinical application.-Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201800131RR

Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response

Mesenchymal stromal cells (MSCs) have attracted intense interest due to their powerful intrinsic properties of self-regeneration, immunomodulation and multi-potency, as well as being readily available and easy to isolate and culture. Notwithstanding, MSC based therapy suffers reduced efficacy due to several challenges which include unfavorable microenvironmental factors in vitro and in vivo. In the quest to circumvent these challenges, several modification techniques have been applied to the naive MSC to improve its inherent therapeutic properties. These modification approaches can be broadly divided into two groups to include genetic modification and preconditioning modification (using drugs, growth factors and other molecules). This field has witnessed great progress and continues to gather interest and novelty. We review these innovative approaches in not only maintaining, but also enhancing the inherent biological activities and therapeutics of MSCs with respect to migration, homing to target site, adhesion, survival and reduced premature senescence. We discuss the application of the improved modified MSC in some selected human diseases. Possible ways of yet better enhancing the therapeutic outcome and overcoming challenges of MSC modification in the future are also elaborated. The importance of prosurvival and promigratory abilities of MSCs in their therapeutic applications can never be overemphasized. These abilities are maintained and even further enhanced via MSC modifications against the inhospitable microenvironment during culture and transplantation. This is a turning point in MSC-based therapy with promising preclinical studies and higher future prospect.

/pdf/improved-therapeutics-of-modified-mesenchymal-stem-cells-an-2k7urbozfp.pdf

Improved therapeutics of modified mesenchymal stem cells: an update

Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.

MSC Based Therapies-New Perspectives for the Injured Lung.

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.

/pdf/mesenchymal-stem-cell-therapy-for-acute-respiratory-distress-1cl16i26ig.pdf

Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics.

The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.

https://www.mdpi.com/2227-9059/8/11/461/pdf

Radioprotection and Radiomitigation: From the Bench to Clinical Practice.

Objective To study the effect of different doses of radiation on intestinal injury,with an attempt to find the optimal radiation dose for establishing intestinal injury models in NOD/SCID mice. Methods Forty healthy male SPF-grade NOD/SCID mice were divided randomly into four groups:blank control group and 4-,5-,6-Gy irradiatio groups,with 10 mice in each group. The irradiation rate was 1 Gy/min. The general conditions,body weight,intestinal bacterial translocation,and histopathologic changes were observed and compared. Results The survival rate was 60%,50%,and 30% in the 4-,5-,and 6-Gy groups 15 days after irradiation,and the intestinal bacterial translocation rate was 20%,50%,and 70%,respectively. The body weights in 5-Gy group (P=0.015) and 6-Gy group (P=0.011) were significantly higher than that in blank control group. The length of small intestinal villi decreased in the 4-Gy group. In the 5-Gy group,the structure of intestinal mucosa villi became wide,flat,and inverted,along with the shedding of epithelial cells,the atrophy of glands,and the damage of recess structures. In the 6-Gy group,the structure of intestinal mucosal villi was damaged,the villi were ruptured and smashed,and the recess structures were missing;meanwhile,there was a large amount of inflammatory cell infiltration between tissues,along with visible spotty bleeding and necrosis. The length of small intestine villi in the blank control group and 4-,5-,and 6-Gy groups were (361.77±22.77),(291.68±32.45),(248.03±51.09),and (195.90±26.39) μm,respectively. In particular,it was significantly shorter in 4-Gy group (P=0.005),5-Gy group (P<0.001),and 6-Gy (P<0.001) than in the blank control group,was significantly shorter in the 5-Gy group (P=0.041) and 6-Gy group (P=0.001) than in the 4-Gy group,and significantly shorter in 6-Gy group than in the 5-Gy group (P=0.020). Conclusion 5-Gy irradiation in mice models can decrease body weight,cause the damage of intestinal mucosa and the shedding of inflammatory cells,with stable survival rate and bacterial translocation rate.

Effect of Different Doses of Radiation on Intestinal Injury in NOD/SCID Mice.

The utility model discloses an auto blood reinfusion device, including vascular suction nozzle, pipeline, anticoagulant bag, the negative pressure pipe stores up blood ware and washing liquid bag, said negative pressure pipe one end with store up the blood ware and connect and communicate with each other, the other end is used for connecting installation vacuum device, it has the centrifugation cup through pipeline installation to store up the blood ware, be connected with the washing liquid bag for centrifugal glass and communicate with each other, the centrifugation cup is connected through pipeline and storage blood bag, pipeline installation has the filter between centrifugation cup and the storage blood bag, the centrifugation cup still is connected with the waste liquid bag. This auto blood reinfusion device, but install a filtering tumor cells's filter additional before ordinary auto blood reinfusion device's storage blood bag tumor cells can effectively be got rid of and to the unobvious influence of the collection of red blood cell to the filter. Tumor cells has effectively been solved and to the influence of the collection of red blood cell to be applicable to various blood transfusion patients.

Auto blood reinfusion device

Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene–modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-β1, and the oxidative stress fa...

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.

Although the role of platelet‐rich plasma (PRP) in ultraviolet light B (UVB)‐induced photoaging has been confirmed in many studies, the specific mechanism is still not clear. Therefore, we attempted to investigate the effect and mechanism of PRP on UVB‐induced human keratinocyte (HaCaT cells) apoptosis.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jocd.15559

Platelet‐rich plasma protects human keratinocytes from UVB‐induced apoptosis by attenuating inflammatory responses and endoplasmic reticulum stress

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Effect of Different Doses of Radiation on Intestinal Injury in NOD/SCID Mice.

Auto blood reinfusion device

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.

Platelet‐rich plasma protects human keratinocytes from UVB‐induced apoptosis by attenuating inflammatory responses and endoplasmic reticulum stress