Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
 
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2020, Vol. 11 Issue (2) : 216-228     DOI: 10.14336/AD.2020.0228
Orginal Article |
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.
Download: PDF(1473 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    
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.

Keywords COVID-19      ACE2 negative      mesenchymal stem cells      cell transplantation      immunomodulation      function recovery     
Corresponding Authors: Liu Hongjian,Jin Ronghua,Jin Kunlin,Zhao Robert Chunhua   
About author:

These authors contributed equally to this work.

Just Accepted Date: 29 February 2020   Issue Date: 13 March 2020
Service
E-mail this article
E-mail Alert
RSS
Articles by authors
Leng Zikuan
Zhu Rongjia
Hou Wei
Feng Yingmei
Yang Yanlei
Han Qin
Shan Guangliang
Meng Fanyan
Du Dongshu
Wang Shihua
Fan Junfen
Wang Wenjing
Deng Luchan
Shi Hongbo
Li Hongjun
Hu Zhongjie
Zhang Fengchun
Gao Jinming
Liu Hongjian
Li Xiaoxia
Zhao Yangyang
Yin Kan
He Xijing
Gao Zhengchao
Wang Yibin
Yang Bo
Jin Ronghua
Stambler Ilia
Lim Lee Wei
Su Huanxing
Moskalev Alexey
Cano Antonio
Chakrabarti Sasanka
Min Kyung-Jin
Ellison-Hughes Georgina
Caruso Calogero
Jin Kunlin
Zhao Robert Chunhua
Cite this article:   
Leng Zikuan,Zhu Rongjia,Hou Wei, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. Aging and disease, 2020, 11(2): 216-228.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2020.0228     OR
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  Clinical classification of the COVID-19 released by the National Health Commission of China.
Figure 1.  The flow chart of the cell transplantation treatment.
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  The general information of the enrolled patients.
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  Symptoms, signs and maximum body temperatures of the critically severe patient from Jan 21 to Feb 13, 2020. ICU: Intensive Care Unit; NA: Not Available.
Figure 2.  Chest computerized tomography (CT) images of the critically severe COVID-19 patient. On Jan 23, no pneumonia performance was observed. On Jan 30, ground-glass opacity and pneumonia infiltration occurred in multi-lobes of the double sides. Cell transplantation was performed on Jan 31. On Feb 2, the pneumonia invaded all through the whole lung. On Feb 9, the pneumonia infiltration faded away largely. On Feb 15, only little ground-glass opacity was residual locally.
Figure 3.  The profile of the peripheral blood mononuclear cells of patients. The mass cytometry results of peripheral blood mononuclear cells of the enrolled patients (A, B) and the critically severe patient (C). No increase of regulatory T cells (CXCR3-) or dendritic cells (DC, CXCR3-) for the two patients of common type (Patients 4 and 5, Figrue 3A). But in the severe patients, both the regulatory T cells and DC increased after the cell therapy, especially for the critically severe patient 1 (Figure 3B). Moreover, for the critically severe patient 1, before the MSC transplantation the percentages of overactivated CXCR3+CD4+ T cells (#9), CXCR3+CD8+ T cells (#17), and CXCR3+ NK cells (#12) in the patient’s PBMC were remarkably increased compared to the healthy control (Figure 3C). However, 6 days after MSC transplantation, the overactivated T cells and NK cells nearly disappeared and the numbers of the other cell subsets were almost reversed to the normal levels, especially the CD14+CD11c+CD11bmid DC (#20) population. Normal: healthy individuals, MSCs: mesenchymal stem cells transplant group, Ctrl: placebo control group.
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  The laboratory results of the critically severe patient. Red: the value was above the normal. Blue: the value was below the normal. NA: Not Available.
Figure 4.  The profile of serum cytokine/chemokine/growth factors. The ratio of serum cytokines IL-10 (A), growth factor VEGF (B), the chemokine IP-10 (C) and TNF-α (D) before and after MSCs treatment were detected in severe patients compared with the control group without MSCs by panel assay analysis, respectively. Ctrl: placebo control group. P-values were determined using Student’s t-test. *P < 0.05.
Figure 5.  RNA-seq analysis of transplanted MSCs. The 10 x RNA-seq survey of MSCs genes expression: Both ACE2 (A) and TMPRSS2 (B) were rarely expressed. TGF-β (C), HGF (D), LIF (E), GAL (F), NOA1 (G), FGF (H), VEGF (I), EGF (J), BDNF (K), and NGF (L) were highly expressed, indicating the immunomodulatory function of MSCs. SPA (M) and SPC (N) were highly expressed, indicating MSCs possessed the ability to differentiate into the alveolar epithelial cells II. One point represented one cell, and red and gray color showed high expression and low expression, respectively.
Figure 6.  ACE2- MSCs benefit the COVID-19 patients via immunoregulatory function.
[1] Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E (2020). A Novel Coronavirus Emerging in China — Key Questions for Impact Assessment. New England Journal of Medicine.
[2] Xu X, Chen P, Wang J, Feng J, Zhou H, Li X et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission.SCIENCE CHINA Life Sciences.
[3] Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet (London, England).
[4] Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature.
[5] Kuba K, Imai Y, Rao SA, Gao H, Guo F, Guan B, et al. (2005). A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine, 11:875-879.
[6] Ge X-Y, Li J-L, Yang X-L, Chmura AA, Zhu G, Epstein JH, et al. (2013). Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature, 503:535-+.
[7] Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S (2020). The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv:2020.2001.2031.929042.
[8] Glowacka I, Bertram S, Mueller MA, Allen P, Soilleux E, Pfefferle S, et al. (2011). Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response. Journal of Virology, 85:4122-4134.
[9] Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N (2019). TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. Journal of Virology, 93.
[10] Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. Journal of Pathology, 203:631-637.
[11] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395:497-506
[12] Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al. (2012). Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurology, 11:150-156.
[13] Wilson JG, Liu KD, Zhuo NJ, Caballero L, McMillan M, Fang XH, et al. (2015). Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respiratory Medicine, 3:24-32.
[14] Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, et al. (2016). Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematology, 3:E45-E52.
[15] Kamen DL, Nietert PJ, Wang H, Duke T, Cloud C, Robinson A, et al. (2018). CT-04βSafety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosus: results of an open-label phase I study. Lupus Science &amp; Medicine, 5:A46-A47.
[16] Galipeau J, Sensebe L (2018). Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell, 22:824-833.
[17] Bernardo ME, Fibbe WE (2013). Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Cell Stem Cell, 13:392-402.
[18] Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM (2010). A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One, 5:e10088.
[19] Li W, Ren G, Huang Y, Su J, Han Y, Li J, et al. (2012). Mesenchymal stem cells: a double-edged sword in regulating immune responses. Cell Death Differ, 19:1505-1513.
[20] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. (2020). Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA.
[21] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet (London, England).
[22] Chen L, Zhang W, Yue H, Han Q, Chen B, Shi M, et al. (2007). Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34(+) cells. Stem Cells and Development, 16:719-731.
[23] Liu X, Qu X, Chen Y, Liao L, Cheng K, Shao C, et al. (2012). Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IL-10-Dependent Regulatory Dendritic Cells by SOCS3 Activation. Journal of Immunology, 189:1182-1192.
[24] Liu X, Ren S, Ge C, Cheng K, Zenke M, Keating A, et al. (2015). Sca-1(+)Lin(-)CD117(-) Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch-RBP-J Signaling. Journal of Immunology, 194:4298-4308.
[25] Zhang B, Liu R, Shi D, Liu X, Chen Y, Dou X, et al. (2009). Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood, 113:46-57.
[26] Sproston NR, Ashworth JJ (2018). Role of C-Reactive Protein at Sites of Inflammation and Infection. Frontiers in Immunology, 9.
[27] Bisoendial RJ, Boekholdt SM, Vergeer M, Stroes ESG, Kastelein JJP (2010). C-reactive protein is a mediator of cardiovascular disease. European Heart Journal, 31:2087-U1505.
[1] Supplementary data Download
[1] Shijin Xia, Changxi Zhou, Bill Kalionis, Xiaoping Shuang, Haiyan Ge, Wen Gao. Combined Antioxidant, Anti-inflammaging and Mesenchymal Stem Cell Treatment: A Possible Therapeutic Direction in Elderly Patients with Chronic Obstructive Pulmonary Disease[J]. Aging and disease, 2020, 11(1): 129-140.
[2] Linsha Ma, Jingchao Hu, Yu Cao, Yilin Xie, Hua Wang, Zhipeng Fan, Chunmei Zhang, Jinsong Wang, Chu-Tse Wu, Songlin Wang. Maintained Properties of Aged Dental Pulp Stem Cells for Superior Periodontal Tissue Regeneration[J]. Aging and disease, 2019, 10(4): 793-806.
[3] Yoorim Choi, Dong Suk Yoon, Kyoung-Mi Lee, Seong Mi Choi, Myon-Hee Lee, Kwang Hwan Park, Seung Hwan Han, Jin Woo Lee. Enhancement of Mesenchymal Stem Cell-Driven Bone Regeneration by Resveratrol-Mediated SOX2 Regulation[J]. Aging and disease, 2019, 10(4): 818-833.
[4] Hongling Li, Junfen Fan, Linyuan Fan, Tangping Li, Yanlei Yang, Haoying Xu, Luchan Deng, Jing Li, Tao Li, Xisheng Weng, Shihua Wang, Robert Chunhua Zhao. MiRNA-10b Reciprocally Stimulates Osteogenesis and Inhibits Adipogenesis Partly through the TGF-β/SMAD2 Signaling Pathway[J]. Aging and disease, 2018, 9(6): 1058-1073.
[5] Wang Jue, Cao Bin, Zhao Haiping, Feng Juan. Emerging Roles of Ganoderma Lucidum in Anti-Aging[J]. Aging and disease, 2017, 8(6): 691-707.
[6] Yan Liang, Gao Rui, Liu Yang, He Baorong, Lv Shemin, Hao Dingjun. The Pathogenesis of Ossification of the Posterior Longitudinal Ligament[J]. Aging and disease, 2017, 8(5): 570-582.
[7] Long Qianfa, Luo Qiang, Wang Kai, Bates Adrian, Shetty Ashok K.. Mash1-dependent Notch Signaling Pathway Regulates GABAergic Neuron-Like Differentiation from Bone Marrow-Derived Mesenchymal Stem Cells[J]. Aging and disease, 2017, 8(3): 301-313.
[8] Li Jiao, Liu Xingyu, zuo Bin, Zhang Li. The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis[J]. Aging and disease, 2016, 7(4): 514-525.
Viewed
Full text


Abstract

Cited

  Shared   
Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail: editorial@aginganddisease.org
Powered by Beijing Magtech Co. Ltd