The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the ensuing worldwide pandemic. The spread of the virus has had global effects such as activity restriction, economic stagnation, and collapse of healthcare infrastructure. Severe SARS-CoV-2 infection induces a cytokine storm, leading to acute respiratory distress syndrome (ARDS) and multiple organ failure, which are very serious health conditions and must be mitigated or resolved as soon as possible. Mesenchymal stem cells (MSCs) and their exosomes can affect immune cells by inducing anti-inflammatory macrophages, regulatory T and B cells, and regulatory dendritic cells, and can inactivate T cells. Hence, they are potential candidate agents for treatment of severe cases of COVID-19. In this review, we report the background of severe cases of COVID-19, basic aspects and mechanisms of action of MSCs and their exosomes, and discuss basic and clinical studies based on MSCs and exosomes for influenza-induced ARDS. Finally, we report the potential of MSC and exosome therapy in severe cases of COVID-19 in recently initiated or planned clinical trials of MSCs (33 trials) and exosomes (1 trial) registered in 13 countries on ClinicalTrials.gov.

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The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

Background Liver cirrhosis is an end-stage multiple liver disease. Mesenchymal stem cells (MSCs) are an attractive cell source for reducing liver damage and regressing fibrosis; additional therapies accompanying MSCs can potentially enhance their therapeutic effects. Kampo medicines exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the therapeutic effect of MSCs combined with the Kampo medicine Juzentaihoto (JTT) as a combination therapy in a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. Methods C57BL/6 mice were administered JTT (orally) and/or MSCs (one time, intravenously). The levels of liver proteins were measured in the sera. Sirius Red staining and hydroxyproline quantitation of hepatic tissues and immune cells were conducted, and their associated properties were evaluated. Liver metabolomics of liver tissues was performed. Results JTT monotherapy attenuated liver damage and increased serum albumin level, but it did not effectively induce fibrolysis. JTT rapidly reduced liver damage, in a dose-dependent manner, after a single-dose CCl4 administration. Furthermore, JTT-MSC combination therapy attenuated liver damage, improved liver function, and regressed liver fibrosis. The combination increased the CD4+/CD8+ ratio. JTT had stronger effects on NK and regulatory T cell induction, whereas MSCs more strongly induced anti-inflammatory macrophages. The combination therapy further induced anti-inflammatory macrophages. JTT normalized lipid mediators, and tricarboxylic acid cycle- and urea cycle-related mediators effectively. Conclusions The addition of JTT enhanced the therapeutic effects of MSCs; this combination could be a potential treatment option for cirrhosis.

We herein report a rare case of HCC metastases to the ovary and peritoneum in a 61-year-old female patient who has achieved 11-year survival with multidisciplinary therapy. The patient was diagnosed with HCC during balloon angioplasty performed for Budd–Chiari syndrome in 1994 and underwent partial hepatectomy twice. Five years after the second hepatectomy, allochronic recurrence of a single nodule detected in S8 was treated by radiofrequency ablation, followed by percutaneous ethanol injection therapy and stereotactic body radiotherapy. However, her α-fetoprotein level rose to 1862 ng/mL within one year and computed tomography revealed a large pelvic tumor suggesting HCC metastasis to the ovary. The subsequent laparotomy revealed one 11-cm left ovarian tumor, one small right ovarian nodule, and numerous peritoneal nodules. Bilateral salpingo-oophorectomy and peritoneal resection of as many nodules as possible were performed. Combination therapy with intravenous 5-fluorouracil plus cisplatin and ramucirumab monotherapy effectively suppressed tumor progression with maintenance of hepatic functional reserve, and she has achieved long-term survival of 11 years, illustrating that multidisciplinary therapy with favorable hepatic functional reserve maintenance can contribute to long-term survival in HCC with extrahepatic spread.