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
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.
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 trials
Australian New Zealand Clinical Trials Registry (ANZCTR)
Brazilian Clinical Trials Registry (ReBec)
Chinese Clinical Trial Registry (ChiCTR)
Clinical Research Information Service (CRiS), Republic of Korea
United States National Library of Medicine
Clinical Trials Registry - India (CTRI)
Cuban Public Registry of Clinical Trials (RPCEC)
EU Clinical Trials Register (EU-CTR)
German Clinical Trials Register (DRKS)
Iranian Registry of Clinical Trials (IRCT)
Japan Primary Registries Network (JPRN)
Thai Clinical Trials Registry (TCTR)
Lebanese Clinical Trials Registry (LBCTR)
The Netherlands National Trial Register (NTR)
Pan African Clinical Trial Registry (PACTR)
Peruvian Clinical Trial Registry (REPEC)
Sri Lanka Clinical Trials Registry (SLCTR)
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)
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
Clinical Trial for Human Mesenchymal Stem Cells in the Treatment of Severe Novel Coronavirus Pneumonia (COVID-19)
Clinical trials of mesenchymal stem cells for the treatment of pneumonitis caused by novel coronavirus pneumonia (COVID-19)
Umbilical cord mesenchymal stem cells (hucMSCs) in the treatment of high-risk novel coronavirus pneumonia (COVID-19) patients
Clinical study for stem cells in the treatment of severe novel coronavirus pneumonia (COVID-19)
Clinical study of human umbilical cord mesenchymal stem cells in the treatment of novel coronavirus pneumonia (COVID-19) induced pulmonary fibrosis
Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected With COVID-19
A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia
Not yet Recruiting
Treatment of COVID-19 Patients Using Wharton’s Jelly-Mesenchymal Stem Cells
NestCell® Mesenchymal Stem Cell to Treat Patients With Severe COVID-19 Pneumonia (HOPE)
Not yet Recruiting
Safety and Efficacy of CAStem for Severe COVID-19 Associated With/Without ARDS
Clinical Research of Human Mesenchymal Stem Cells in the Treatment of COVID-19 Pneumonia
Safety and Efficacy Study of Allogeneic Human Dental Pulp Mesenchymal Stem Cells to Treat Severe COVID-19 Patients
Treatment With Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)
Novel Coronavirus Induced Severe Pneumonia Treated by Dental Pulp Mesenchymal Stem Cells
Not yet Recruiting
Umbilical Cord (UC)-Derived Mesenchymal Stem Cells (MSCs) Treatment for the 2019-novel Coronavirus (nCOV) Pneumonia
Table 2 Selected trials in ICTP of WHO.
Protocol design: Selected Trials with Randomized Controlled Design
Phase / Target participants
Phase 0 / 30 subjects
Experimental group: conventional treatment combined with umbilical cord mesenchymal stem cellconditioned medium group Control group: Conventional treatment
Phase 1-2 / 30 Subjects
Experimental 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
Phase 1-2 / 20 Subjects
Experimental 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
Phase 2 / 90 Subjects
Experimental 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
Phase 2 / 60 subjects
Experimental 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
Total target Participants
Experimental group: mesenchymal stem cells. Control group: saline. Note: Randomly divided into group A as placebo group and group B as stem cell treatment group
Experimental group: Conventional medication + Infusion of mesenchymal stem cells; Control group: Conventional medication.
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
Phase / Target Participants
Phase 1 / 20 Subjects
parallel open label
Experimental 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.
Phase 1 / 30 Subjects
MSCs-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).)
Phase 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.
Phase 1 / 66 Subjects
single arm open label
NestCell® is a mesenchymal stem cell therapy produced by Cellavita
Phase 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.
Phase 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.
Conventional treatment (CT) combined with UC-MSC conditioned medium
Severe or/to critical pneumonia diagnosis due to SARS-CoV infection
CT + UC-MSC CT + placebo
Severe Novel Coronavirus Pneumonia
MSCs or saline
Moderate to severe cases of new coronavirus pneumonia
Patients with high risk
CT or CT plus UC-MSCs
Severe novel coronavirus pneumonia
CT + UC-MSCs
on days 0, 3, and 6 for a total of 3 times
Novel Coronavirus Pneumonia (COVID-19) severity not mentioned
CT plus MSCs
at Day 0, Day 3, Day 6).
Pneumonia Patients Infected With COVID-19 severity not mentioned
CT plus MSCs-derived exosomes
1*108 nano vesicles/3 ml
at Day 1, Day 2, Day 3, Day 4, Day 5
Severe or/to critical pneumonia diagnosis due to SARS-CoV infection
The three doses will be 3 days apart form each other. 3 weeks follow up
CAStem, immunity- and matrix-regulatory cells (IMRCs), differentiated from hESCs
3/5/10*106 cells/kg. Escalating doses.
intervals not mentioned
3 cohorts with 3 patients/cohort with severe COVID-19 associated w/wo ARDS.
CT plus MSCs
1 time, or with an interval of 1 week
Critically ill COVID-19 pneumonia
CT plus hDP-MSCs
3*107cells/bag * 3 bags
injection of on day 1, day 4 and day 7
Severe pneumonia caused by COVID-19
CT plus MSCs
at Day 0, Day 3, Day 6.
COVID-19 Patients with Severe Convalescence
CT plus hDP-MSCs
1.0x106 cells /kg.
on day 1, 3 and 7 of the trial.
Novel Coronavirus Induced Severe Pneumonia
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).
Comments on PROS
Comments on CONS
They are easily accessible and can be isolated from various tissues
The 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.
They are multipotent stem cells
Adult 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.
MSCs can easily expand to clinical volume in a suitable period of time
Safety Concerns of using transformed cells
In 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.
MSCs can be stored for repetitive therapeutic usage
Choosing autologous or non-autologous human cells
Regardless 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 issues
Clinical trials of MSCs so far haven’t shown adverse reactions to allogeneic MSC.
Maintenance of cell viability
The 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.
Effectiveness 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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