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Aging and disease  2020, Vol. 11 Issue (2): 216-228    DOI: 10.14336/AD.2020.0228
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Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Zikuan Leng1,5, Rongjia Zhu2, Wei Hou3, Yingmei Feng3, Yanlei Yang4, Qin Han2, Guangliang Shan2, Fanyan Meng1, Dongshu Du1, Shihua Wang2, Junfen Fan2, Wenjing Wang3, Luchan Deng2, Hongbo Shi3, Hongjun Li3, Zhongjie Hu3, Fengchun Zhang4, Jinming Gao4, Hongjian Liu5,*, Xiaoxia Li6, Yangyang Zhao2, Kan Yin6, Xijing He7, Zhengchao Gao7, Yibin Wang7, Bo Yang8, Ronghua Jin3,*, Ilia Stambler9,10,11, Lee Wei Lim9,10,12, Huanxing Su9,10,13, Alexey Moskalev9,10,14, Antonio Cano9,10,15, Sasanka Chakrabarti16, Kyung-Jin Min9,10,17, Georgina Ellison-Hughes9,10,18, Calogero Caruso9,10,19, Kunlin Jin9,10,20,*, Robert Chunhua Zhao1,2,9,10,*
1School of Life Sciences, Shanghai University, Shanghai, 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.
5Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 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.
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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.

Key wordsCOVID-19    ACE2 negative    mesenchymal stem cells    cell transplantation    immunomodulation    function recovery
收稿日期: 2020-02-25      出版日期: 2020-03-13
引用本文:   
. [J]. Aging and disease, 2020, 11(2): 216-228.
Zikuan Leng, Rongjia Zhu, Wei Hou, Yingmei Feng, Yanlei Yang, Qin Han, Guangliang Shan, Fanyan Meng, Dongshu Du, Shihua Wang, Junfen Fan, Wenjing Wang, Luchan Deng, Hongbo Shi, Hongjun Li, Zhongjie Hu, Fengchun Zhang, Jinming Gao, Hongjian Liu, Xiaoxia Li, Yangyang Zhao, Kan Yin, Xijing He, Zhengchao Gao, Yibin Wang, Bo Yang, Ronghua Jin, Ilia Stambler, Lee Wei Lim, Huanxing Su, Alexey Moskalev, Antonio Cano, Sasanka Chakrabarti, Kyung-Jin Min, Georgina Ellison-Hughes, Calogero Caruso, Kunlin Jin, Robert Chunhua Zhao. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and disease, 2020, 11(2): 216-228.
链接本文:  
http://www.aginganddisease.org/CN/10.14336/AD.2020.0228      或      http://www.aginganddisease.org/CN/Y2020/V11/I2/216
MildCommonSevereCritically severe
Mild clinical manifestation,
None Imaging Performance
Fever,
respiratory symptoms, pneumonia performance on X-ray or CT
Meet any of the followings:
1. Respiratory distress, RR ≥ 30/min; 2. Oxygen saturation ≤ 93% at rest state; 3. Arterial partial pressure of oxygen (PaO2) / Fraction of inspiration O2 (FiO2) ≤ 300mnHg, 1mmHg=0.133kPa
Meet any of the followings:
1. Respiratory failure needs mechanical ventilation; 2. Shock; 3. Combined with other organ failure, patients need ICU monitoring and treatment
Table 1  
Figure 1.  
Case 1Case 2Case 3Case 4Case 5Case 6Case 7Ctrl 1Ctrl 2Ctrl 3
GenderMFFFMMMFFF
Age (years)65636551574553757446
COVID-19 typeCritically severeSevereSevereCommonCommonSevereSevereSevereSevereSevere
Fever (?, baseline)38.637.738.238.538.439.039.036.038.937.7
Shortness of breath++++++++++++++++++++++
Oxygen saturation at rest state89%93%92%95%94%92%90%91%92%93%
Cough, weak, poor appetite++++++++++++++++
Diarrhea--+-------
Date of diagnosedJan 23Jan 27Jan 25Feb 3Feb 2Jan 27Feb 3Feb 3Feb 6Feb 5
Date of intervention
(MSCs or Placebo)
Jan 31Feb 2Feb 4Feb 4Feb 4Feb 6Feb 6Feb 8Feb 6Feb 6
Date of recoveryFeb 3Feb 4Feb 6
Discharged
Feb 6
Discharged
Feb 5
Discharged
Feb 7Feb 7DeadARDSStable
Table 2  
HomeHospitalHospitalICUICUICUICUICUOut of ICUHospitalHospital
DateJan 21~22Jan 23Jan 24~29Jan 30Jan 31Feb 1Feb 2~3Feb 4Feb 5~8Feb 9~12Feb 13
Fever (?)37.537.837.0~38.538.638.836.836.6~36.936.836.6~36.836.5~36.936.6
Shortness of breath-+++++++++++----
Cough+++++++++----
Sputum+++++++++----
O2 saturation
(without/with O2 uptake)
NA/NANA/NA97% /NA91%/ 95%89% /94%NA /98%NA /97%NA /96%NA /97%96% //NA97% /NA
Respiratory rateNA2323273322222120~2220~2221
Treatment
(Basics-1: Antipyretic, antiviral and supportive therapy. Basics-2: antiviral and supportive therapy)
NANABasics-1Basics-1; Mask O2 5L/minBasics-1; Mask O2 10L/min; Cell transplantBasics-1; Mask O2 5L/minBasics-2;
Mask O2 5L/min
Basics-2;
Mask O2 5L/min
Basics-2; Mask O2 5L/minBasics-2Basics-2
RT-PCR of the virusNAPositiveNANANANANANAPositive
(Feb 6)
NANegative
Table 3  
Figure 2.  
Figure 3.  
Reference rangeJan 24Jan 30Jan 31Feb 1Feb 2Feb 4Feb 6Feb 10Feb 13
C-reactive protein (ng/mL)< 3.002.20105.50NA191.0083.4013.6022.7018.3010.10
Absolute lymphocyte count (× 109/L)1.10-3.200.940.600.350.230.350.580.870.730.93
White-cell count (× 109/L)3.50-9.504.916.357.907.0812.1612.5711.2610.658.90
Absolute neutrophil count (× 109/L)1.80-6.303.435.437.286.6311.3311.109.439.187.08
Absolute monocyte count (× 109/L)0.10-0.600.380.250.170.130.350.610.520.480.56
Red-cell count (× 1012 /L)4.30-5.804.694.684.664.784.734.755.164.694.53
Hemoglobin (g/L)130.00-175.00145.00147.00145.00146.00142.00145.00155.00145.00137.00
Platelet count (× 109/L)125.00-350.00153.00148.00169.00230.00271.00268.00279.00332.00279.00
Absolute eosinophil count (× 109/L)0.02-0.520.020.020.020.020.020.050.150.140.14
Absolute basophilic count (× 109/L)0.00-0.060.020.010.020.020.020.060.100.030.04
Total bilirubin (μmol/L)5.00-21.007.0023.0021.7019.8014.2015.8016.5012.508.70
Albumin (g/L)40.00-55.0041.7032.3029.7029.9031.6033.0032.2030.1029.10
Aspartate amino transferase (U/L)15.00-40.0014.0033.0048.0057.0039.0034.0023.0025.0019.00
Fibrinogen (g/L)2.00-4.002.444.24NANA4.73NA3.123.843.73
Procalcitonin (ng/mL)< 0.100.110.12NANANA0.100.180.15< 0.10
Creatine kinase isoenzymes (ng/mL)< 3.600.900.12NA5.674.24NA0.880.900.61
Creatine kinase (U/L)50.00-310.00168.00231.00NA513.00316.00NA47.0083.0040.00
Glomerular filtration rate (ml/min)> 90.0081.3068.0089.6099.00104.0092.50108.1097.1094.10
Potassium (mmol/L)3.50-5.303.612.743.003.423.474.184.364.694.61
Sodium (mmol/L)137.00-147.00138.50132.60129.50132.80136.90135.80133.80134.10137.70
Myoglobin (ng/mL)16.00-96.0053.0080.00NA138.0077.00NA62.0060.0043.00
Troponin (ng/mL)< 0.0560.100.07NA0.050.05NA0.020.040.04
Table 4  
Figure 4.  
Figure 5.  
Figure 6.  
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