Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Authors: Bo Yang
Luchan Deng
Lee Wei Lim
Huanxing Su
Kan Yin
Zhengchao Gao
Shihua Wang
Wei Hou
Yanlei Yang
Sasanka Chakrabarti
Yingmei Feng
Kyung-Jin Min
Fengchun Zhang
Antonio Cano
Ilia Stambler
Qin Han
Dongshu Du
Hongjian Liu
Ronghua Jin
Yibin Wang
Alexey Moskalev
Xijing He
Zikuan Leng
Hongjun Li
Georgina Ellison-Hughes
Guangliang Shan
Jinming Gao
Robert Chunhua Zhao
Xiaoxia Li
Rongjia Zhu
Kunlin Jin
Hongbo Shi
Zhongjie Hu
Junfen Fan
Wenjing Wang
Calogero Caruso
Fanyan Meng
Yangyang Zhao
Journal: Aging and disease (2020)
Discipline: CLINICAL MEDICINE
Keywords: ACE2 negative; COVID-19; cell transplantation; function recovery; immunomodulation
Affiliations: 1School of Life Sciences, Shanghai University, Shanghai, China., 5Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China., 3Beijing YouAn Hospital, Capital Medical University, Beijing, China., 4Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China., 6Institute of Stem Cell and Regeneration Medicine, School of Basic Medicine, Qingdao University, Shandong, China., 7Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., 8Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., 9The Executive Committee on Anti-aging and Disease Prevention in the framework of Science and Technology, Pharmacology and Medicine Themes under an Interactive Atlas along the Silk Roads, UNESCO, Paris, France., 10International Society on Aging and Disease, Fort Worth, Texas, USA., 11The Geriatric Medical Center "Shmuel Harofe", Beer Yaakov, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel., 12School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China., 13Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China., 14Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia., 15Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain., 16Maharishi Markandeshwar Deemed University, Mullana-Ambala, India., 17Department of Biological Sciences, Inha University, Incheon, South Korea., 18Faculty of Life Sciences & Medicine, King's College London, London, UK., 19Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy., 20University of North Texas Health Science Center, Fort Worth, TX76107, USA.

Abstract:  A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition. 

Retracted: No

PubPeer comments:
 In this paper, mesenchymal stem cells (MSCs) are investigated as a tool to treat patients with COVID-19 pneumonia in Beijing YouAn Hospital. This is an interesting study in times where there are still very few good treatment options for coronavirus-caused pneumonia. It is also unrealistic to expect well-performed studies with high numbers of patients in both treatment and control group, since the need for new therapy options is high and time is short. However, some parts of the paper might be worth discussing here. 1. The study included 7 patients treated with MSC (all of whom recovered), and 3 treated with placebo control (1 died, 1 with ARDS (abbreviation not defined), and 1 stable ). This is not a very well balanced study setup. COVID-19 cases appear to be quite erratic with some people recovering quickly and with others severely ill. With such low numbers, it might be hard to know what is signal and what is noise 2. The 7 treatment cases had an average age of 57 (range: 45-65), while the 3 control cases had an average age of 65 (range: 46-75). While this might not seem like a big difference, the control group had 2 patients over 70 years old, while none of the treated patients were older than 65. Age is a huge risk factor in COVID-19 mortality rate, so this might be an important confounding factor, which was not discussed as all as a potential weakness of the study. Of note, the control patient who died was 75 years old (the oldest of all 10 patients), while the control patient with ARDS was 74 years old (the second oldest person of all 10). ![file] 3. The Methods state: *Patients were ineligible if they had been diagnosed with any kind of cancers or the doctor declared the situation to belong to the critically severe condition.* Except for excluding cancer, there is no description of underlying conditions, such as being immunocompromised or other preexisting disease that might be of influence of the COVID-19 infection outcome. Could the authors please clarify if all patients were healthy before they got the coronavirus infection? 4. Related to 3), 8 of the 10 patients are described as  severe or  critically severe - how does that match the eligibility description? 5. The time interval between date of diagnosis and date of intervention appears to be different between treatment and control groups as well. For the treatment group it was 5.7 days, but for the control group only 2.0 days. Could this be a confounding factor as well? 6. The paper has 38 authors from 20 different institutes from China, France, USA, Israel, Russia, Spain, India, South Korea, UK, and Italy. Did all authors qualify for authorship as per ICMJE guidelines? See: http: www.icmje.org recommendations browse roles-and-responsibilities defining-the-role-of-authors-and-contributors.html It seems hard to imagine how 20 different institutes worked together to do an MSC transplant on 10 patients, even with the additional mass cytometry and RNAseq analysis. Could the authors please describe the role of all 38 authors? 7. The Methods are very short. In particular, essential data is missing on the type of MSC that were used. If other people want to save their patients they might need to know a bit more details. Did they come from one particular donor? ,