Stem Cell Therapy: a Promising Treatment For COVID-19 > 자유게시판

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Author contributions: Zheng ZX contributed to writing the manuscript, drafting conception and design.

Corresponding creator: Zhi-Xue Zheng, MD, Doctor, Surgeon, Surgical Oncologist, Department of General Surgery, Beijing Jishuitan Hospital, No. 31 Xinjiekou East Street, Beijing 100035, China. pollitzheng@sina.com

Received 2021 Mar 26; Revised 2021 May 12; Accepted 2021 Aug 23; Issue date 2021 Dec 26.

This article is an open-entry article which was chosen by an in-house editor and absolutely peer-reviewed by exterior reviewers. It's distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, construct upon this work non-commercially, and license their derivative works on completely different terms, offered the original work is correctly cited and the use is non-industrial.

Novel coronavirus illness 2019 (COVID-19) attributable to extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has grow to be a global pandemic. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. COVID-19 can result in a cytokine storm and patients usually have early respiratory indicators and further secondary infections, which could be fatal. COVID-19 has entered an emergency phase, but there are nonetheless no specific efficient medicine for this disease. Mesenchymal stem cells (MSCs) are multipotent stromal cells, which trigger antiapoptosis and may repair broken epithelial cells. Many clinical trials have proved that MSC therapy might be a potential feasible therapy for COVID-19 patients, especially those with acute respiratory distress syndrome, without serious adversarial occasions or toxicities. However, more studies are needed sooner or later, with a view to verify the impact of this therapy.

Keywords: COVID-19, SARS-CoV-2, Mesenchymal stem cells, Pandemic, Stem cell therapy

Core tip: Coronavirus illness 2019 (COVID-19) has turn out to be a worldwide pandemic and entered an emergency part. However, there are nonetheless no particular efficient medicine for the COVID-19. Many earlier studies have shown that mesenchymal stem cell transplantation is a promising choice for COVID-19-contaminated patients, and further research need to be performed sooner or later.

Novel coronavirus disease 2019 (COVID-19) is a severe respiratory illness that was first identified in December 2019 in Wuhan, China. COVID-19 is brought on by extreme acute respiratory syndrome coronavirus (SARS-CoV)-2 and has change into a worldwide pandemic. To this point, > one hundred million SARS-CoV-2 infections and > 2 million deaths have been reported by the World Health Organization (WHO)[1,2]. It has been established that SARS-CoV-2 has sequence homology with SARS-CoV-1, one of many coronaviruses found in bats[3-7].

SARS-CoV-2 is without doubt one of the Coronaviridae family of viruses, which incorporates four varieties, α, β, γ and δ. SARS-CoV-2, SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV),belong to the β group[4,8]. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. The angiotensin-changing enzyme (ACE)2, a membrane receptor, binds the S protein. ACE2 is highly expressed on lung alveolar kind II cells, and is commonly found in heart, liver, kidney and digestive system cells, however not in bone marrow, spleen, lymph nodes and macrophages[9,10]. The transmembrane protease, serine 2 is also generally expressed on sort II lung cells, which may initiate S protein and help the virus to invade host cells[6,10].

Furthermore, this viral infection results in cytokine release syndrome, also called cytokine storm, and will increase the level of inflammatory cytokines [interleukin (IL)-2, IL-6, IL-8, IL-17, tumor necrosis issue (TNF)-α, granulocyte colony-stimulating issue (CSF), granulocyte-macrophage CSF], and chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, interferon-induced protein 10)[11-13]. Consequently, patients show early indicators of fever, cough, headache, followed by high fever, pulmonary edema, difficult respiratory, acute respiratory distress syndrome (ARDS) and additional secondary infections, which can result in potentially fatal penalties[14-17]. COVID-19 usually affects the upper and lower respiratory tract with an incubation period of two wk. The analysis of SARS-CoV-2 infection is based on an RT-PCR take a look at and particular IgM and IgG in patients[18-20]. However, there are still no specific drugs for treating this infection at current.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that may differentiate into many various kinds of cells including chondrocytes, osteoblasts and adipocytes, which has been confirmed in quite a lot of cells. MSCs are often found in bone marrow, umbilical cord, placenta, adipose fat pads and dental pulp[21,22]. MSCs, which secrete numerous cytokines and chemokines, trigger antiapoptosis, and may restore damaged epithelial cells[23,24]. MSCs secrete cytokines and modulate the immune response by regulating cell perform and downregulating inflammatory cytokines in graft versus host disease and systemic lupus erythematous [25,26]. Therefore, MSCs could also be a possible treatment for COVID-19, as they could transfer towards injured lung cells and restore them.

MSCs have proved effective in both experimental research and clinical research, including many immune-mediated inflammatory diseases, with good security and low risk[23,24]. Previous research have proven that MSCs might reduce H5N1 influenza virus in older patients with acute lung damage, and enhance the survival price of H7N9-infected patients with ARDS without severe complications[27,28]. MSCs can even intervene in the activation of inflammatory cytokine secretion in dendritic cells (DCs)[29,30]. Ling et al[31] discovered that stage-particular embryonic antigen-1, stem cell antigen-1, cytokeratin-7 and ACE2 had been expressed in lung epithelial cells and ACE2 was expressed in lung stem cells. Furthermore, SARS-CoV-infected lung cells that lacked differentiated stem cells failed to restore. For this reason, MSC transplantation could also be a possible therapy for COVID-19.

MSC THERAPY FOR COVID-19

The COVID-19 pandemic has entered an emergency phase, however there are still no particular effective drugs for this infection[32]. As a result of lack of efficient therapy for COVID-19, present therapy relies on particular person symptoms and supportive remedy. Most patients obtain oxygen therapy and extracorporeal membrane oxygenation is advisable for refractory hypoxemia[33].

At current, medication for COVID-19 include antiviral drugs, antimalarial medicine, anti-human immunodeficiency virus medication, anti-inflammatory medication, and monoclonal antibodies, corresponding to remdesivir, chloroquine, lopinavir/ritonavir, nitazoxanide, and conventional Chinese medicine, which have been utilized in China and western international locations[34-41]. Many research on IL-1, IL-2, IL-6 and TNF-α medicine have demonstrated that they will suppress the inflammatory response in COVID-19 patients, and have provided some clues on anti-inflammatory therapy to treat SARS-CoV-2 infection with higher outcomes[42]. Etoposide-primarily based therapy has been proposed as a brand new therapy for COVID-19, which requires further clinical trials[43]. There are at present several ongoing clinical trials of medication and vaccines for the remedy of COVID-19.

Zheng et al[44] confirmed that MSC therapy for ARDS resulted in no infusion toxicity or severe adverse occasions. Another examine involving patients with ARDS who had been handled with an infusion of allogenic bone-marrow-derived human MSCs demonstrated good safety and no treatment-related adversarial events. Furthermore, this therapy decreased lung damage in a sheep model[23,45]. Therefore, MSC-primarily based therapy demonstrated promising outcomes for ARDS with none prespecified adverse events, and was each tolerable and secure. However, there are not any lengthy-time period knowledge on MSC-therapy-associated opposed events[46,47].

CD147 is a marker of undifferentiated embryonic stem cells, and is the second entry receptor for SARS-CoV-2. Its protein is expressed in tissue-particular stem cells of human bone marrow origin. Inhibition of CD147 can forestall inflammatory processes in diabetic complications[48,49]. SARS-CoV-2 infection can trigger pulmonary fibrosis in normal tissue, and probably originates from resident stem cells, that are additionally known as MSC-like cells. In the early stage of COVID-19 pneumonia, type II pneumocytes are involved in the preliminary step of pulmonary fibrosis. Anti-CD147 antibodies that may suppress the normal lung cell differentiation of fibroblasts in vitro have been investigated, and MSC transplantation might lead to immunosuppression and tissue regeneration[50,51].

In the primary study of MSCs, Leng et al[14] handled seven patients with COVID-19 pneumonia with an injection of MSCs, and confirmed a big discount in clinical symptoms and a lower in serum proinflammatory cytokines with out adversarial results. Many of the patients had been unfavorable on the SARS-CoV-2 nucleic acid check within 2 wk after MSCs transplantation. Chen et al[52] noticed that each one patients confirmed clinical enchancment, including 64% of patients with chest CT improvement, but little enchancment in immunomodulation and cardiotoxicity throughout MSC therapy.

Human umbilical cord-derived MSC (UC-MSC) transplantation has been carried out in COVID-19 patients. A feminine patient with extreme COVID-19 was treated with an human UC-MSC injection, which resulted in good efficacy without side effects[53]. Twelve patients with extreme COVID-19 treated with UC-MSC transplantation reported enhancements in clinical consequence, reduced C-reactive protein and IL-6 ranges, and no mortality[54,55]. A Phase I clinical trial of UC-MSCs for COVID-19 discovered no severe hostile events, and lung lesions in 4 average-extreme patients fully disappeared within 2 wk after injection[56]. Adipose-tissue-derived MSCs have been used to deal with 13 severe COVID-19 pneumonia patients, and 70% of patients had clinical improvement and reduced levels of inflammatory elements[57]. Tang et al[58] used menstrual-blood-derived MSCs to deal with extreme COVID-19 patients, and located that bilateral pulmonary exudation had been absorbed and SaO2 and PO2 have been also improved. Similar to MSCs, immunity- and matrix-regulatory cells (IMRCs) even have self-renewal and mesenchymal differentiation capability. Following injection of IMRCs, COVID-19 patients recovered and examined negative for the virus, while many inflammatory cytokines reminiscent of IFN-α2, IL-3, M-CSF and TNF-α had been suppressed[59]. Previous research have shown that MSC therapy could activate the immune system, stem cells can repair tissues, after which forestall the cytokine storm and launch anti-inflammatory mediators. Consequently, this may occasionally forestall pulmonary fibrosis caused by SARS-CoV-2 infection. The MSCs had been resistant to viral infection as a consequence of expression of interferon-stimulated genes [60-62]. The traits of included studies are shown in Table 1.

Characteristics of included stem cell studies of Coronavirus disease 2019

COVID-19: Coronavirus illness 2019; MSCs: Mesenchymal stem cells; UC-MSCs: Umbilical cord-derived MSCs; Ad-MSCs: Adipose tissue-derived MSCs; MB-MSCs: Menstrual blood-derived MSCs; CT: Computed tomography.

Recent studies have indicated that MSCs are in a position to secrete immunomodulatory components that would suppress the cytokine storm, promote tissue regeneration and inhibit tissue fibrosis. Given the earlier preclinical and clinical research, MSC therapy has shown good safety and efficacy within the therapy of respiratory failure or ARDS[63,64]. Therefore, MSC injection showed promising results for therapy of COVID-19 patients[65]. In addition, many clinical trials on MSCs for COVID-19 (NCT04315987, NCT04313322 and NCT04333368) are ongoing worldwide. More clinical information will assist this efficient therapy. However, the variety of patients in these studies is small, and the long-term security and efficacy of this remedy require additional investigation. The consistency of MSC high quality cannot be assured, and the dose was also inconsistent in these research. The heterogeneity, secretory and immunomodulatory capabilities of MSCs are unclear; therefore, the outcomes from totally different research are tough to match. Further examine would develop clinical preparation and treatment requirements for MSCs in COVID-19 patients, and larger numbers of patients stay to be included in MSCs studies.

MSC transplantation has proved to be a promising selection for COVID-19 patients, and more studies must be accomplished sooner or later. This therapy has been shown to have few unintended effects. MSCs could also be a protected and effective therapeutic technique, or as part of a combination therapy for COVID-19 patients.

Conflict-of-interest statement: The creator declared there aren't any conflicts of curiosity to this work.

Provenance and peer assessment: Invited article; Externally peer reviewed.

Peer-assessment mannequin: Single blind

Peer-assessment began: March 26, 2021

First determination: May 12, 2021

Article in press: August 23, 2021

Specialty kind: Infectious diseases

Country/Territory of origin: China

Grade B (Superb): B

Grade C (Good): Zero

P-Reviewer: Kashyap MK S-Editor: Wu YXJ L-Editor: Kerr C P-Editor: Yu HG

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