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Aging and disease    2020, Vol. 11 Issue (5) : 1174-1191     DOI: 10.14336/AD.2020.0608
Review Article |
Stem Cell Based Therapy Option in COVID-19: Is It Really Promising?
Duygu Koyuncu Irmak1,2,*, Hakan Darıcı1,2,3, Erdal Karaöz1,2,3,4
1Istinye University, Faculty of Medicine, Department of Histology & Embryology, Istanbul, Turkey
2Istinye University, Stem Cell and Tissue Engineering R&D Center, Istanbul, Turkey
3Istinye University, 3D Bioprinting Design & Prototyping R&D Center, Istanbul, Turkey
4Liv Hospital, Stem Cell and Regenerative Therapies Center (LivMedCell), Istanbul, Turkey
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Abstract  

The COVID-19 patients were first detected in China, in December 2019, then the novel virus with associated pneumonia and other diseases spread quickly to worldwide becoming a serious public health intimidation. Despite all the efforts, the pharmacological agents used for controlling or treating the disease, especially respiratory problems, have not been accomplished so far. Among various treatment options, mesenchymal stem cell-based cellular therapies are being investigated, because of their regeneration ability and multipotency along with other features like immunomodulation, antifibrosis and anti-inflammatory effects. This paper intends to analyze the current clinical trials on stem cell treatment of novel virus, searching and reviewing the available information and the International Clinical Trials Registry Platform (ICTRP) of World Health Organization (WHO). We concluded that the stem cell treatment of COVID-19 is found promising with pilot studies’ results, but still in the early development phase. There is an urgent need for large-scale investigations to confirm and validate the safety and efficacy profile of these therapies with reliable scientific evidence.

Keywords Stem cell      treatment      COVID-19      clinical      trials     
Corresponding Authors: Irmak Duygu Koyuncu   
About author:

These authors contributed equally to this work.

Just Accepted Date: 07 August 2020   Issue Date: 21 September 2020
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Irmak Duygu Koyuncu
Darıcı Hakan
Karaöz Erdal
Cite this article:   
Irmak Duygu Koyuncu,Darıcı Hakan,Karaöz Erdal. Stem Cell Based Therapy Option in COVID-19: Is It Really Promising?[J]. Aging and disease, 2020, 11(5): 1174-1191.
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http://www.aginganddisease.org/EN/10.14336/AD.2020.0608     OR
Figure 1.  Demonstration of the SARS-CoV impact during the general immune reaction function. (PRRs: pattern recognition receptors, TLR: Toll-like receptor, NLR: NOD)-like receptors, RLR: retinoic acid-inducible gene-I (RIG-I)-like receptors, IFN: Interferone).
Registry of Clinical trialsWeb Site
1Australian New Zealand Clinical Trials Registry (ANZCTR)http://www.anzctr.org.au/
2Brazilian Clinical Trials Registry (ReBec)http://www.ensaiosclinicos.gov.br/
3Chinese Clinical Trial Registry (ChiCTR)http://www.chictr.org.cn/index.aspx
4Clinical Research Information Service (CRiS), Republic of Koreahttp://ctri.nic.in/Clinicaltrials/login.php
5United States National Library of Medicinehttps://www.clinicaltrials.gov
6Clinical Trials Registry - India (CTRI)http://ctri.nic.in/Clinicaltrials/login.php
7Cuban Public Registry of Clinical Trials (RPCEC)http://registroclinico.sld.cu/en/home
8EU Clinical Trials Register (EU-CTR)https://www.clinicaltrialsregister.eu/
9German Clinical Trials Register (DRKS)https://www.drks.de/drks_web/
10Iranian Registry of Clinical Trials (IRCT)https://www.irct.ir/
11Japan Primary Registries Network (JPRN)https://rctportal.niph.go.jp/en/
12Thai Clinical Trials Registry (TCTR)http://www.clinicaltrials.in.th/
13Lebanese Clinical Trials Registry (LBCTR)http://lbctr.emro.who.int/Trials/View#
14The Netherlands National Trial Register (NTR)https://www.trialregister.nl/
15Pan African Clinical Trial Registry (PACTR)https://pactr.samrc.ac.za/
16Peruvian Clinical Trial Registry (REPEC)https://ensayosclinicos-repec.ins.gob.pe/en/
17Sri Lanka Clinical Trials Registry (SLCTR)http://www.slctr.lk/
Table 1  Clinical trials and web sites.
Figure 1.  First step trial selection by searching in the International Clinical Trials Registry Platform (ICTRP) of WHO with COVID-19, Coronavirus, New Coronavirus, SARS-CoV-19 key words. The clinical trials are either excluded or selected based on the study type (interventional and treatment trials are selected) and study phase (only the trials whose phase of development mentioned are selected. The further selection is done by the additional key word of stem cell and finally 16 trials are selected as a result of first step trial selection. (search date: 18 April 2020)
Trial IDPublic titleRecruitment StatusInclusion age
minmax
ChiCTR2000029569Safety 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 trialNot Recruiting18-
ChiCTR2000030138Clinical Trial for Human Mesenchymal Stem Cells in the Treatment of Severe Novel Coronavirus Pneumonia (COVID-19)Not Recruiting1675
ChiCTR2000029990Clinical trials of mesenchymal stem cells for the treatment of pneumonitis caused by novel coronavirus pneumonia (COVID-19)Recruiting1895
ChiCTR2000030300Umbilical cord mesenchymal stem cells (hucMSCs) in the treatment of high-risk novel coronavirus pneumonia (COVID-19) patientsRecruiting1875
ChiCTR2000031494Clinical study for stem cells in the treatment of severe novel coronavirus pneumonia (COVID-19)Recruiting1890
ChiCTR2000031430Clinical study of human umbilical cord mesenchymal stem cells in the treatment of novel coronavirus pneumonia (COVID-19) induced pulmonary fibrosisRecruiting1880
NCT04252118Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected With COVID-19Recruiting1870
NCT04276987A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus PneumoniaNot yet Recruiting1875
NCT04313322Treatment of COVID-19 Patients Using Wharton’s Jelly-Mesenchymal Stem CellsRecruiting18-
NCT04315987NestCell® Mesenchymal Stem Cell to Treat Patients With Severe COVID-19 Pneumonia (HOPE)Not yet Recruiting18-
NCT04331613Safety and Efficacy of CAStem for Severe COVID-19 Associated With/Without ARDSRecruiting1870
NCT04339660Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 PneumoniaRecruiting1875
NCT04336254Safety and Efficacy Study of Allogeneic Human Dental Pulp Mesenchymal Stem Cells to Treat Severe COVID-19 PatientsRecruiting1865
NCT04288102Treatment With Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)Recruiting1875
NCT04302519Novel Coronavirus Induced Severe Pneumonia Treated by Dental Pulp Mesenchymal Stem CellsNot yet Recruiting1875
NCT04269525Umbilical Cord (UC)-Derived Mesenchymal Stem Cells (MSCs) Treatment for the 2019-novel Coronavirus (nCOV) PneumoniaRecruiting1875
Table 2  Selected trials in ICTP of WHO.
Protocol design: Selected Trials with Randomized Controlled Design
Trial IDPhase / Target participantsBlindingIntervention
ChiCTR2000029569Phase 0 /
30 subjects
Open labelExperimental group: conventional treatment combined with umbilical cord mesenchymal stem cellconditioned medium group
Control group: Conventional treatment
NCT04339660Phase 1-2 /
30 Subjects
Triple-blindedExperimental group: conventional and treatment with umbilical cord MSCs,
1x106 UC-MSCs /kg body weight suspended in 100mL saline Control group: conventional treatment and Placebo intravenously. Placebo 100mL saline intravenously
NCT04336254Phase 1-2 /
20 Subjects
Triple-blindedExperimental group: allogeneic human dental pulp stem cells
Intravenous injection of 3.0x107 human dental pulp stem cells solution (30ml) on day 1, day 4 and day 7, based on routine treatment of COVID-19 Control group: Intravenous saline injection as Placebo Intravenous injection of 3ml of 0.9% saline on day 1, day 4 and day 7, based on routine treatment of COVID-19
NCT04288102Phase 2 /
90 Subjects
Quadruple-blindedExperimental Group: Conventional treatment plus 3 times of MSCs(4.0x107 cells per time) intravenously at Day 0, Day 3, Day 6.
Control Group: Saline containing 1% Human serum albumin (solution of MSC) 3 times of placebo (intravenously at Day 0, Day 3, Day 6)Other: Intravenous saline injection (Placebo) Intravenous injection of 3ml of 0.9% saline on day 1, day 4 and day 7, based on routine treatment of COVID-19
ChiCTR2000030138Phase 2 /
60 subjects
Double BlindedExperimental group: Intravenous injection of human umbilical cord mesenchymal stem cells (UC-MSC); Note: routine treatment combination was not mentioned in the other records.
Control Group: Routine treatment + placebo
Table 3  The randomised controlled trials along with their development phases, participant size blinding status and the treatment intervention types to cure SARS-CoV infection in ICTP database of WHO.
Protocol design: Selected Trials with Parallel Controlled Design
Trial IDPhaseTotal target ParticipantsIntervention
ChiCTR2000029990Phase 1-2120 SubjectsExperimental group: mesenchymal stem cells.
Control group: saline. Note: Randomly divided into group A as placebo group and group B as stem cell treatment group
ChiCTR2000031494Phase 136 SubjectsExperimental group: Conventional medication + Infusion of mesenchymal stem cells;
Control group: Conventional medication.
ChiCTR2000031430Phase 2200 SubjectsExperimental group: Conventional treatment regimen + MSC treatment;
Control group: Conventional treatment regimen.
Table 4  The Parallel Controlled Design along with their development phases, participant size blinding status and the treatment intervention types to cure SARS-CoV infection in ICTP database of WHO.
Protocol design: Selected Trials with Other Design Characteristics
Trial IDPhase / Target ParticipantsDesignIntervention
NCT04252118Phase 1 /
20 Subjects
parallel open labelExperimental Group: 3 times of MSCs (3.0*10E7 MSCs intravenously at Day 0, Day 3, Day 6).
Control Group: Without MSCs Therapy but conventional treatment should be received.
NCT04276987Phase 1 /
30 Subjects
Single armMSCs-derived exosomes
(5 times aerosol inhalation of MSCs-derived exosomes (2.0*10E8 nano vesicles/3 ml at Day 1, Day 2, Day 3, Day 4, Day 5).)
NCT04313322Phase 1 /
5 Subjects
Single arm
open label
WJ-MSCs will be derived from cord tissue of newborns, screened for HIV1/2, HBV, HCV, CMV, Mycoplasma, and cultured to enrich for MSCs.
NCT04315987Phase 1 /
66 Subjects
single arm
open label
NestCell® is a mesenchymal stem cell therapy produced by Cellavita
NCT04331613Phase 1-2 /
9 Subjects
single arm
open label
CAStem will be administered intravenously.
Human Embryonic Stem Cells Derived M Cells (CAStem) A dose-escalation with 3 cohorts with 3 patients/cohort who receive doses of 3, 5 or 10 million cells/kg. If there are no safety concerns for each cohort, the dose will be escalated from lower dose to next higher dose.
NCT04302519Phase early 1 /
24 Subjects
single arm
open label
Dental pulp mesenchymal stem cells
On the basis of clinical standard treatment, the injection of dental mesenchymal stem cells was increased on day 1, 3 and 7 of the trial.
Table 5  The trials with other design characteristics along with their development phases, participant size blinding status and the treatment intervention types to cure SARS-CoV infection in ICTP database of WHO.
Trial IDTherapyRouteDoseApplication intervalsCondition
ChiCTR2000029569Conventional treatment (CT) combined with UC-MSC conditioned mediumNot mentionedNot mentionedNot MentionedSevere or/to critical pneumonia diagnosis due to SARS-CoV infection
ChiCTR2000030138CT + UC-MSC
CT + placebo
IV injectionNot mentionedNot MentionedSevere Novel Coronavirus Pneumonia
ChiCTR2000029990MSCs or salineNot mentionedNot mentionedNot MentionedModerate to severe cases of new coronavirus pneumonia
ChiCTR2000030300 (Cancelled)(UC-MSCs)Not mentionedNot mentionedNot MentionedPatients with high risk
ChiCTR2000031494CT or CT plus UC-MSCsIVNot mentionedNot MentionedSevere novel coronavirus pneumonia
ChiCTR2000031430CT + UC-MSCsIV4*107 cells/applicationon days 0, 3, and 6 for a total of 3 timesNovel Coronavirus Pneumonia (COVID-19) severity not mentioned
NCT04252118CT plus MSCsIV1*107cells/applicationat Day 0, Day 3, Day 6).Pneumonia Patients Infected With COVID-19 severity not mentioned
NCT04276987CT plus MSCs-derived exosomesaerosol inhalation1*108 nano vesicles/3 mlat Day 1, Day 2, Day 3, Day 4, Day 5Severe or/to critical pneumonia diagnosis due to SARS-CoV infection
NCT04313322WJ-MSCsIV1*106 cells/kgThe three doses will be 3 days apart form each other. 3 weeks follow upCOVID-19 (ever, respiratory destress, pneumonia, cough, sneezing, diarrhea) severity not mentioned
NCT04313322WJ-MSCsIV1*10e6 cells/kgThe three doses will be 3 days apart form each other.COVID-19 (ever, respiratory destress, pneumonia, cough, sneezing, diarrhea) severity not mentioned.
NCT04315987CT plus MSCsIV2*107cells/applicationon days 1, 3 and 5 and if necessary on day 7Severe COVID-19 pneumonia.
NCT04331613CAStem, immunity- and matrix-regulatory cells (IMRCs), differentiated from hESCsIV3/5/10*106 cells/kg. Escalating doses.intervals not mentioned3 cohorts with 3 patients/cohort with severe COVID-19 associated w/wo ARDS.
NCT04339660CT plus MSCsIV1*106 cells/kg1 time, or with an interval of 1 weekCritically ill COVID-19 pneumonia
NCT04336254CT plus hDP-MSCsIV3*107cells/bag * 3 bagsinjection of on day 1, day 4 and day 7Severe pneumonia caused by COVID-19
NCT04288102CT plus MSCsIV4.0*107at Day 0, Day 3, Day 6.COVID-19 Patients with Severe Convalescence
NCT04302519CT plus hDP-MSCsIV1.0x106 cells /kg.on day 1, 3 and 7 of the trial.Novel Coronavirus Induced Severe Pneumonia
NCT04269525UC-MSCsIV3.3*107/50ml bags*3bag,on day 1, day 3, day 5, and day 7.Serious Pneumonia and Critical Pneumonia Caused by the 2019-nCOV Infection
Table 6  The MSC treatment doses, route of administration, treatment/ application intervals and target lung condition’s name and grade (mild, moderate, severe or critical).
PROSComments on PROSCONSComments on CONS
AccessibilityThey are easily accessible and can be isolated from various tissuesCell SourcingThe cell-based therapies need the cells need to be expanded in large quantities while protecting their uniformity in activity and staying pathogen free. The use of human embryonic stem (ES) cells versus adult SCs is still a matter of debate. The current political decision makers strongly favoring adult stem cell option.
PotencyThey are multipotent stem cellsPlasticityAdult SCs have certain plasticity to transdifferentiate from one lineage pathway to another. Besides, instead of transdifferentiating with normal diploid chromosomal numbers, SCs may fuse with tissue-specific differentiated cells causing polyploidy. MSCs differentiation was reported to lead to tissue ossification or calcification in animal models which is also a potential risk in human use.
VolumeMSCs can easily expand to clinical volume in a suitable period of timeSafety Concerns of using transformed cellsIn children with adenosine deaminase deficiency, the autologous transplantation of genetically modified hematopoietic stem cells was reported to lead to severe immunodeficiency followed by acute leukemia in some of the patients. Nerve cells implantation in Parkinson’s disease patients was reported the high rate of severe and uncontrollable dyskinetic activity as adverse effect. Also, myoblast implantation into the heart tissue showed adverse event of increased rates of cardiac arrhythmias.
StorageMSCs can be stored for repetitive therapeutic usageChoosing autologous or non-autologous human cellsRegardless of the chosen method, each treatment has important regulatory and practical difficulties, and logistics of delivery can be another issue, i.e. to maintain the uniformity of cells, to avoid any contamination during cell processing.
No Reported Safety issuesClinical trials of MSCs so far haven’t shown adverse reactions to allogeneic MSC.Maintenance of cell viabilityThe nutrient and oxygen delivery to the cellular implant is of vital importance for viability of the cells. It has been still in experimental stage to use the neovascular capillary bed in and around the cell implant and intravascular cell encapsulation implant approach not having use in human in clinics.
EffectivenessEffectiveness of MSCs have been obviously documented in several clinical trials*The references used to compile the information for this table: 22, 33, 77, 78, 79, 80, 81.
Table 7  The Pros and Cons of MSCs use for treatment purposes in general*.
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