Mesenchymal Stem Cells in COVID-19

A Journey From Bench to Bedside

Kamal Kant Sahu, MD; Ahmad Daniyal Siddiqui, MD; Jan Cerny, MD, PhD

Lab Med. 2021;52(1):24-35.

Abstract and Introduction

Abstract

The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.

Introduction

As of June 3, 2020, there were 6,551,389 global COVID-19 cases with 386,196 deaths. Although approximately 98% of patients experience mild disease, 2% experience severe disease often requiring critical care support.^[1,2]

To date, physicians and intensivists treating patients with COVID-19 have limited treatment options in the absence of an effective antiviral agent or vaccine.^[3–5] Therapeutic options in the form of convalescent plasma therapy, remdesivir, tocilizumab, and repurposing of various drugs are being explored.^[6–10] Recently, a few studies have examined the role of mesenchymal stem cells (MSCs) in critically ill patients with COVID-19. These studies have shown some early promise as therapeutic possibilities for the treatment of severe COVID-19.^[11–14]

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Next Section

Table 1. List of Registered Cell-Based Clinical Trials for Treating COVID-19 Worldwide
ClinicalTrials.gov Identifier	Title	Study Characteristics	Primary Outcome Measures	Responsible Party
United States
NCT04299152	Clinical Application of Stem Cell Educator Therapy for the Treatment of Viral Inflammation Caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)	—Interventional study —Estimated participants: 20 —Study design: parallel	Determine the number of patients with COVID-19 who were unable to complete SCE therapy (time frame: 4 weeks)	Tianhe Stem Cell Biotechnologies Inc., China
NCT04348435	A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Determine the Safety and Efficacy of Hope Biosciences Allogeneic Mesenchymal Stem Cell Therapy (HB-adMSCs) to Provide Protection Against COVID-19	—Interventional study —Estimated participants: 100 —Study design: parallel	—Incidence of hospitalization for COVID-19 (time frame: week 0 through week 26 [end of study]) —Incidence of symptoms associated with COVID-19 (time frame: week 0 through week 26 [end of study])	Hope Biosciences Stem Cell Research Foundation, Sugar Land, TX
NCT04355728	Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS)	—Interventional study —Estimated participants: 12 —Study design: parallel	—Incidence of prespecified infusion-associated AEs (time frame: day 5) —Incidence of SAEs (time frame: 90 days)	Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
NCT04345601	Single Donor Banked Bone Marrow Mesenchymal Stromal Cells for the Treatment of SARS-CoV-2 Induced Acute Respiratory Failure: A Pilot Study	—Interventional study —Estimated participants: 30 —Intervention model: single group	—Incidence of unexpected AEs (time frame: 28 days post—cell infusion) —Improved oxygen saturations ≥ 93% (time frame: within 7 days of cell infusion)	Houston Methodist Hospital, Houston, TX
China
ChiCTR2000031319	Safety and Efficacy Study of Allogeneic Human Dental Pulp Mesenchymal Stem Cells to Treat Severe Pneumonia of COVID-19: a Single-center, Prospective, Randomised Clinical Trial	—Interventional study —Estimated participants: 20 —Study design: parallel	…	Center for Regenerative Medicine, Renmin Hospital of Wuhan University, China
ChiCTR2000031735	Clinical study for natural killer (NK) cells from umbilical cord blood in the treatment of viral pneumonia include novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 20 —Study design: parallel	Monitoring of AEs within 24 hours after infusion (including infusion-related events and SAEs associated with nonprimary disease)	Huzhou Central Hospital, Zhejiang, China
ChiCTR2000031139	Safety and Effectiveness of Human embryonic stem cell-derived M cells (CAStem) for Pulmonary Fibrosis Correlated with novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 20 —Study design: sequential	—Pulmonary function evaluation —Changes in blood gas analysis —Evaluation of activity —Evaluation of dyspnea	Wuhan Jinyintan Hospital (Wuhan Infectious Diseases Hospital), Wuhan, Hubei, China
ChiCTR2000030509	Clinical Study of NK Cells in the Treatment of Novel Coronavirus Pneumonia (COVID-19)	—Interventional study —Estimated participants: 40 —Study design: parallel	Time and rate of novel coronavirus become negative	The First Hospital of Harbin Medical University, Harbin, Heilongjiang, China
ChiCTR2000030329	Clinical trial for umbilical cord blood CIK and NK cells in the treatment of mild and general patients infected with novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 90 —Study design: parallel	—Status of immune function —Nucleic acid test is negative —Length of stay in hospital	The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China
ChiCTR2000030224	Clinical study of mesenchymal stem cells in treating severe novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 32 —Study design: parallel	—Inflammatory biomarkers —Blood routine —Temperature —Lesions of lung seen in CT scan	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
ChiCTR2000030173	Key techniques of umbilical cord mesenchymal stem cells for the treatment of novel coronavirus pneumonia (COVID-19) and clinical application demonstration	—Interventional study —Estimated participants: 60 —Study design: parallel	—Pulmonary function —Novel coronavirus pneumonic nucleic acid test	Nanhua Hospital, affiliated with Nanhua University, Hengyang, Hu'nan, China
ChiCTR2000030088	Umbilical cord Wharton's Jelly derived mesenchymal stem cells in the treatment of severe novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 40 —Study design: parallel	—Nucleic acid test for novel coronavirus is negative —CT scan of ground glass shadow disappeared	The Sixth Medical Center of PLA General Hospital, Beijing, China
ChiCTR2000030020	The clinical application and basic research related to mesenchymal stem cells to treat novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 40 —Study design: sequential	—Coronavirus nucleic acid markers have negative rate —Inflammation (per chest CT) —Symptoms improved after 4 treatments	Second Hospital of University of South China, Hengyang, China
ChiCTR2000029816	Clinical Study of Cord Blood Mesenchymal Stem Cells in the Treatment of Acute Novel Coronavirus Pneumonia (COVID-19)	—Interventional study —Estimated participants: 60 —Study design: parallel	Time to disease recovery	Guangzhou Reborn Health Management Consultation Co, Ltd, Guangzhou, Guangdong, China
ChiCTR2000029812	Clinical Study for Umbilical Cord Blood Mononuclear Cells in the Treatment of Acute Novel Coronavirus Pneumonia (NCP)	—Interventional study —Estimated participants: 60 —Study design: parallel	Time to disease recovery	Guangzhou Reborn Health Management Consultation Co, Ltd, Guangzhou, Guangdong, China
ChiCTR2000029606	Clinical Study for Human Menstrual Blood-derived Stem Cells in the Treatment of Acute Novel Coronavirus Pneumonia (COVID-19)	—Interventional study —Estimated participants: 63 —Study design: parallel	Mortality in patients	The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
ChiCTR2000029580	Severe novel coronavirus pneumonia (COVID-19) patients treated with ruxolitinib in combination with mesenchymal stem cells: a prospective, single blind, randomized controlled clinical trial	—Interventional study —Estimated participants: 70 —Study design: parallel	Safety	Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
ChiCTR2000029572	Safety and efficacy of umbilical cord blood mononuclear cells in the treatment of severe and critically novel coronavirus pneumonia (COVID-19): a randomized controlled clinical trial	—Interventionalstudy —Estimated participants: 30 —Study design: parallel	PSI	Xiangyang First People's Hospital, Xiangyang, Hubei, China
ChiCTR2000029569	Safety and efficacy of umbilical cord blood mononuclear cells conditioned medium in the treatment of severe and critically novel coronavirus pneumonia (COVID-19): a randomized controlled trial	—Interventional study —Estimated participants: 30 —Study design: parallel	PSI	Xiangyang First People's Hospital, Xiangyang, Hubei, China
CTR2000030116	Safety and effectiveness of human umbilical cord mesenchymal stem cells in the treatment of acute respiratory distress syndrome of severe novel coronavirus pneumonia (COVID-19)	Interventional study —Estimated participants: 16 —Study design: dose comparison	Time to leave ventilator on day 28 after receiving MSC infusion	The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
ChiCTR2000030484	HUMSCs and Exosomes Treating Patients with Lung Injury following Novel Coronavirus Pneumonia (COVID-19)	—Interventional study —Estimated participants: 90 —Study design: parallel	—PaO₂/FiO₂ or respiratory rate (without oxygen) —Frequency of respiratory exacerbation —Observe physical signs and symptoms and record clinical recovery time —Number and range of lesions indicated by CT and X-ray of lung —Time for cough to become mild or absent —Time for dyspnea to become mild or no dyspnea —Frequency of oxygen inhalation or noninvasive ventilation, frequency of mechanical ventilation —Inflammatory cytokines (eg, CRP/PCT/SAA) —Frequency of SAE	Hubei Shiyan Taihe Hospital, Shiyan, Hubei, China
ChiCTR2000030866	Open-label, observational study of human umbilical cord derived mesenchymal stem cells in the treatment of severe and critical COVID-19.	Observational study —Estimated participants: 30 Study design: single arm	-Oxygenation index (PaO₂/FiO₂) —Conversion rate from serious to critical patients —Conversion rate and conversion time from critical to serious patients —Mortality in serious and critical patients	Changsha First Hospital, Changsha, Hu'nan, China
ChiCTR2000030835	Clinical study on the efficacy of Mesenchymal stem cells (MSC) in the treatment of severe novel coronavirus pneumonia (COVID-19)	—Interventional study —Estimated participants: 20 —Study design:single arm	NA	The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China
ChiCTR2000030138	Clinical Trial for Human Mesenchymal Stem Cells in the Treatment of Severe Novel Coronavirus Pneumonia (COVID-19)	—Interventional study —Estimated participants: 60 —Study design: parallel	Clinical index	Chinese PLA General Hospital, Haidian Distract, Beijing, China
NCT04302519	Clinical Study of Novel Coronavirus Induced Severe Pneumonia Treated by Dental Pulp Mesenchymal Stem Cells	—Interventional study —Estimated participants: 24 Study design: single group	Disappear time of ground-glass shadow in lungs (time frame: 14 days)	CAR-T (Shanghai) Biotechnology Co, Ltd, Shanghai, China
NCT04288102	Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Human Mesenchymal Stem Cells in Combination with Standard Therapy in the Treatment of COVID-19 Patients With Severe Convalescence	—Interventional study —Estimated participants: 90 —Study design: parallel	Size of lesion area and severity of pulmonary fibrosis by chest CT (time frame: at baseline, day 6, day 10, day 14, day 28, day 90]	Maternal and Child Hospital of Hubei Province, Wuhan, Hubei, China, and Wuhan Huoshenshan Hospital, Wuhan, Hubei, China
NCT04273646	Clinical Study of Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Severe COVID-19	—Interventional study —Estimated participants: 48 —Study design: parallel	—Pneumonia severity index (time frame: from baseline to 12 weeks after treatment) —Oxygenation index (PaO₂/FiO₂; time frame: from baseline to 12 weeks after treatment)	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
NCT04252118	Safety and Efficiency of Mesenchymal Stem Cell in Treating Pneumonia Patients Infected With COVID-19	—Interventional study —Estimated participants: 20 —Study design: parallel	—Size of lesion area by chest radiograph or CT (time frame: at baseline, day 3, day 6, day 10, day 14, day 21, day 28) —Side effects in MSC treatment group (time frame: at baseline, day 3, day 6, day 10, day 14, day 21, day 28, day 90, day 180)	Beijing 302 Military Hospital of China, Beijing, China
NCT04269525	Clinical Research Regarding the Availability and Safety of UC-MSCs Treatment for Serious Pneumonia and Critical Pneumonia Caused by the 2019-nCOV Infection	—Interventional study —Estimated participants: 10 —Intervention model: single group	Oxygenation index (time frame: on day 14 after enrollment)	Zhongnan Hospital, Wuhan, Hubei, China
NCT04276987	A Pilot Clinical Study on Aerosol Inhalation of the Exosomes Derived From Allogenic Adipose Mesenchymal Stem Cells in the Treatment of Severe Patients With Novel Coronavirus Pneumonia	—Interventional study —Estimated participants: 30 —Intervention model: single group	—Time to clinical improvement (time frame: up to 28 days) —AE and SAE (time frame: up to 28 days)	Ruijin Hospital, Wuhan, China
NCT04346368	Safety and Efficacy of Intravenous Infusion of Bone Marrow-Derived Mesenchymal Stem Cells in Severe Patients with Coronavirus Disease 2019 (COVID-19): A Phase 1/2 Randomized Controlled Trial	—Interventional study —Estimated participants: 20 —Intervention model: Single group	—AEs in BM-MSC treatment group (time Frame: baseline–6 months) —Changes in oxygenation index (PaO₂/FiO₂; time frame: baseline, 6hours, day 1, day 3, week 1, week 2, week 4, month 6)	Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
NCT04339660	Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia	—Interventional study —Estimated participants: 30 —Study design: parallel	—Observe immune function (TNF-α, IL-1β, IL-6, TGF-β, IL-8, PCT, CRP; time frame: within 4 weeks) —Monitor blood oxygen saturation (time frame: within 4 weeks)	Puren Hospital, affiliated with Wuhan University of Science and Technology, Wuhan, Hubei, China
NCT04331613	Safety and Efficacy Study of Human Embryonic Stem Cells Derived M Cells (CAStem) for the Treatment of Severe COVID-19 Associated With or Without Acute Respiratory Distress Syndrome (ARDS)	—Interventional study —Estimated participants: 09 —Study design: single group	—AE and SAE (time frame: within 28 days after treatment) —Changes in lung imaging examinations (time frame: within 28 days after treatment)	Beijing YouAn Hospital, Capital Medical University Beijing, Beijing, China,
Brazil
NCT04315987	Exploratory Clinical Study to Assess the Efficacy of NestCell Mesenchymal Stem Cell to Treat Patients with Severe COVID-19 Pneumonia	—Interventional study —Estimated participants :66 —Study design: single group	Change in clinical condition (time frame: 10 days)	Hospital Vera Cruz Campina Grande, São Paulo, Brazil
Jordan
NCT04313322	Treatment of COVID-19 Patients Using Wharton's Jelly-Mesenchymal Stem Cells	—Interventional study —Estimated participants: 5 —Intervention model: single group	—Improvement of clinical symptoms (time frame: 3 weeks) —AEs measured by chest radiograph/CT scan (time frame: 3 weeks) —RT-PCR results of viral RNA turning negative (time frame: 3 weeks)	Stem Cells Arabia, Amman, Jordan
France
NCT04333368	Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS	—Interventional study —Estimated participants: 60 —Intervention model: single group	Respiratory efficacy evaluated by increase in PaO₂/FiO2 ratio from baseline to day 7 in experimental group compared with placebo group	Hôpital Pitié-Salpêtrière—APHP, Paris, France, and Hôpital Européen Georges Pompidou—APHP, Paris, France
United Kingdom
NCT04349540	A Prospective Non-Interventional Study to Evaluate the Role of Immune and Inflammatory Response in Recipients of Allogeneic Haematopoietic Stem Cell Transplantation (SCT) Affected by Severe COVID19 Infection	—Observational study —Estimated participants: 40 —Intervention model: case-only	…	Great Ormond Street Hospital, NHS Foundation Trust, London, United Kingdom
NCT03042143	Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration (REALIST): An Open Label Dose Escalation Phase 1 Trial Followed by a Randomized, Double-blind, Placebo-controlled Phase 2 Trial (COVID-19)	—Interventional study —Estimated participants: 75 —Study design: parallel	—Oxygenation index (time frame: day 7) —Incidence of SAEs (time frame: 28 days)	Belfast Health and Social Care Trust, Royal Hospitals Belfast, Northern Ireland, United Kingdom
Spain
NCT04348461	Two-treatment, Randomized, Controlled, Multicenter Clinical Trial to Assess the Safety and Efficacy of Intravenous Administration of Expanded Allogeneic Adipose Tissue Adult Mesenchymal Stromal Cells in Critically Ill Patients COVID-19	—Interventional study —Estimated participants: 100 —Study design: parallel	—Efficacy of administration of allogeneic MSCs derived from AT assessed by survival rate (time frame: 28 days) —Safety of administration of allogeneic MSCs derived from AT assessed by AE rate (time frame: 6 months)	Instituto de Investigación, Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
Denmark
NCT04341610	Allogeneic Adipose Tissue Derived Mesenchymal Stromal Cell Therapy for Treating Patients with Severe Respiratory COVID-19. A Danish, Double-blind, Randomized Placebo-controlled Study	—Interventional study —Estimated participants: 40 —Study design: parallel	Changes in clinical critical treatment index (time frame: day 7 from randomization)	Department of Cardiology, The Heart Centre, University Hospital Rigshospitalet, Copenhagen, Denmark

SCE, stem cell educator; AE, adverse event; SAE, serious adverse event; CT, computed tomography; PSI, patient safety indicators; MSCs, mesenchymal stem cells; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; PCT, procalcitonin; SAA, serum amyloid A; CRP, C-reactive protein; BM-MSC, bone marrow mesenchymal stem cells; RT-PCR, real-time polymerase chain reaction; AT, adipose tissue