Different kinds of stem cells in the development of SARS-CoV-2 treatments

Table 1 Resume of organoid infection models developed for severe acute respiratory syndrome coronavirus 2 study

Ref.	Organoid infection model	Reported advantages
Yang et al[15]	hPSC-derived cells/organoids, including pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, cortical neurons, and dopaminergic neurons	Permissiveness to SARS-CoV-2 infection; ACE2 expression was detected; Chemokine induction
Han et al[16]	hPSC-LOs	hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection; Robust chemokine induction; Discovery and test therapeutic drugs
	hPSC-COs	Permissiveness to SARS-CoV-2 infection hPSC-Cos especially enterocytes, express ACE2; Discovery and test therapeutic drugs
Pei et al[18]	hAWOs and hALOs from hESCs	Permissiveness to SARS-CoV-2 infection and replication; Infected cells express ACE2 but not all ACE2 expressing cells were infected; Chemokine induction; Discovery and test therapeutic drugs
Yiangou et al[20]	hPSC-derived cardiac models	Permissiveness to SARS-CoV-2 infection; Activation of the innate inflammatory response; Show contractility, electrophysiology, and sarcomeric fragmentation
Monteil et al[22]	Human capillary organoids from iPSCs; Kidney organoids from hESCs	Permissiveness to SARS-CoV-2 infection and significantly inhibited by human recombinant soluble ACE2. ACE2 expression

hPSC: Human pluripotent stem cells; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2; hPSC-LOs: Lung organoid model using human pluripotent stem cells; hPSC-Cos: hPSC-derived colonic organoids; hAWOs: Human airway organoids; hALOs: Alveolar organoids; iPSCs: Induced pluripotent stem cells; hESCs: Human embryonic stem cells.

Table 2 Clinical trials completed using different types of stem cells or their derivatives

No.	Title	Conditions	Interventions	Locations
1	Study Evaluating the Safety and Efficacy of Autologous Non-Hematopoietic Peripheral Blood SCs in COVID-19	COVID-19	Biological: Autologous NHPBSC; Drug: COVID-19 standard care	Abu Dhabi SCs Center, Abu Dhabi, United Arab Emirates
2	Mesenchymal SCs Therapy in Patients With COVID-19 Pneumonia	COVID-19, Pneumonia	Other: Mesenchymal SCs	University of Health Sciences, Istanbul, Turkey
3	Treatment with Human Umbilical Cord-derived Mesenchymal SCs for Severe Corona Virus Disease 2019 (COVID-19)	COVID-19	Biological: UC-MSCs; Biological: Saline containing 1% Human serum albumin solution without UC-MSCs	General Hospital of Central Theater Command, Wuhan, Hubei, China
4	Mesenchymal SCs for the Treatment of COVID-19	COVID-19, Prophylaxis	Biological: PrimePro (UC-MSCs); Other: Placebo	Southern California Hospital at Culver City/Southern California Hospital at Hollywood, Culver City, California, United States
5	Use of UC-MSCs for COVID-19 Patients	COVID-19, ARDS	Biological: Umbilical Cord Mesenchymal; SCs + Heparin along with best supportive care. Other: Vehicle + Heparin along with best supportive care	Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida, United States
6	Therapeutic Study to Evaluate the Safety and Efficacy of DWMSC in COVID-19 Patients	COVID-19, SAR	Drug: allogeneic mesenchymal stem cell; Other: Placebo	Site 550: University of Hassanudin/Dr. Wahidin Sudirohusodo Hospital, Makassar, Indonesia
7	Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan	COVID-19, Cytokine Release Syndrome, Critical Illness, ARDS	Procedure: Therapeutic Plasma exchange; Biological: Convalescent Plasma; Drug: Tocilizumab; Drug: Remdesivir; Biological: Mesenchymal stem cell therapy	Pak Emirates Military Hospital, Rawalpindi, Punjab, Pakistan
8	Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia.	COVID-19, Pneumonia	Drug: EXO 1 inhalation; Drug: EXO 2 inhalation; Drug: Placebo inhalation	Medical Centre Dinasty, Samara, Russian Federation
9	A Pilot Clinical Study on Inhalation of Mesenchymal SCs Exosomes Treating Severe Novel Coronavirus Pneumonia	COVID-19	Biological: MSCs-derived exosomes	Ruijin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China

United States National Library of Medicine, ClinicalTrials.gov, 02/21/2021. COVID-19: Coronavirus disease 2019; NHPBSC: Non hematopoietic peripheral blood SCs; SCs: Stem cells; MSCs: Mesenchymal stem cells; UC-MSCs: Umbilical cord-derived MSCs; ARDS: Acute respiratory distress syndrome; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 3 Advantages and disadvantages of stem cells in clinical trials

	Advantages	Disadvantages
ESCs
	High differentiation capability which can recapitulate appropriate cell-intrinsic phenotypes	Ethical dilemma
	Grow up in the laboratory from a single cell for later transplantation	Tumorigenesis risk
MSCs
	Immunomodulatory properties	A narrower spectrum of differentiation
	Widespread availability and accessibility	High expression of ACE2 receptor
	Limited ethical concerns	Expression of MHC I and II

ESCs: Embryonic stem cells; MSCs: Mesenchymal stem cells; ACE2: Angiotensin-converting enzyme 2; MHC: Major histocompatibility complex.