Mesenchymal Stem Cells: Case Report of an Adjuvant Ambulatory Therapy for a COVID-19 High-Risk and steroid-hypersensitive Patient.

INTRODUCTION: Due to the rapid progression of COVID-19 to severe and critical stages, thousands of patients have required the use of intensive care unit (ICU) treatment, placing an excessive strain on health systems. Immunomodulatory effects of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) have shown promising results on the treatment of patients with COVID-19. However, the effect of promptly applied cell therapy on ambulatory patient prognosis has not been described. This case report presents the clinical outcome of a multimorbid, steroid-hypersensitive, COVID-19 patient treated with WJ-MSCs transplantation. CASE PRESENTATION: A 67-year-old woman with Type 2 diabetes, overweight (82 kg, 168 cm, BMI = 29.053), hypertension (60/190 mmHg) and steroid-hypersensitivity, tested positive for COVID-19 after presenting typical symptoms such as fatigue, chest pain, myalgia, nasal congestion, dysgeusia, anosmia and oxygen saturation (SpO2) 94% - 96%, with normal body temperature (36°C). The patient received pharmacologic treatment but, when symptoms worsened, WJ-MSCs were transplanted to modulate the suspected onset of the cytokine release syndrome. Significant improvement of symptoms and clinical parameters (inflammatory markers and CT score) were observed, and the patient fully recovered within a short period of time. CONCLUSION: The present case report exhibits the favorable outcome of using Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) as an ambulatory and adjuvant therapy for COVID-19. Prompt WJ-MSCs infusion can be a safe ambulatory adjuvant therapy in COVID-19 infection care, preventing disease progression to critical stages and avoiding hospital overcrowding.

Dissecting the Interrelationship between COVID-19 and Diabetes Mellitus.

COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to enormous morbidity and mortality worldwide. After gaining entry into the human host, the virus initially infects the upper and lower respiratory tract, subsequently invading multiple organs, including the pancreas. While on one hand, diabetes mellitus (DM) is a significant risk factor for severe COVID-19 infection and associated death, recent reports have shown the onset of DM in COVID-19-recovered patients. SARS-CoV-2 infiltrates the pancreatic islets and activates stress response and inflammatory signaling pathways, impairs glucose metabolism, and consequently leads to their death. Indeed, the pancreatic autopsy samples of COVID-19 patients reveal the presence of SARS-CoV-2 particles in ß-cells. The current review describes how the virus enters the host cells and activates an immunological response. Further, it takes a closer look into the interrelationship between COVID-19 and DM with the aim to provide mechanistic insights into the process by which SARS-CoV-2 infects the pancreas and mediates dysfunction and death of endocrine islets. The effects of known anti-diabetic interventions for COVID-19 management are also discussed. The application of mesenchymal stem cells (MSCs) as a future therapy for pancreatic ß-cells damage to reverse COVID-19-induced DM is also emphasized.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Efficacy and Safety of Mesenchymal Stem Cells for COVID-19 Infection: A Meta-Analysis and Systematic Review.

BACKGROUND: COVID-19 (coronavirus disease 2019) is a pandemic around the world, and its treatment options often fail to achieve ideal results. There is a lot of controversy in the treatment of COVID-19 with mesenchymal stem cells (MSCs). The study aims to assess the safety and efficacy of mesenchymal treatment of new coronary pneumonia. METHODS: We manually searched electronic databases including PubMed, Embase, Cochrane Library, and Web of Science until 25th July 2022, and Stata 15.0 (StataCorpLLC: College Station, TX, USA) was used to analyze the data. RESULTS: A total of 8 randomized controlled trials were included, involving a total of 345 people, of which 180 were in the MSCs group and 165 were in the placebo group. The analysis results showed that MSCs can reduce mortality in COVID-19 patients compared to placebo [RR (Risk Ratio) = 0.56, 95% CI (Confidence Interval) (0.36, 0.89); p = 0.003]. There was no significant difference between the mesenchymal stem cell group and the placebo group in the incidence of adverse reactions [RR = 0.64, 95% CI (0.34, 1.18); p = 0.281]; In the SpO2/FiO2 (Oxygen Saturation/Fraction of Inspiration O2) [WMD (Weighted Mean Difference) = 9.07, 95% CI (-38.01, 56.15); p = 0.080]; In ICU (Intensive Care Unit) stay [WMD = -1.66, 95% CI (-7.23, 3.91); p = 0.131]. CONCLUSIONS: Mesenchymal stem cells can reduce the mortality of COVID-19 patients.

The Anti-Viral Activity of Stem Cells: A Rational Explanation for their Use in Clinical Application.

It is well established the importance of stem cells (SCs) in tissue growth, regeneration and repair, given their ability to self-renew and differentiate into mature cells. Stem cells are present in all individuals and are potentially active to the end of life. However, less is known about their unique function within the immune system as immune regulators and their important task in viral protection. Antiviral resistance is a common mechanism in all cells though stem cells utilize an antiviral RNA interference (RNAi) mechanism, while adult cells react by using the interferondependent repression pathway via interferon-associated protein-based response to induce an antiviral response. Therefore, the idea behind this review is to highlight the mechanisms of viral evasion of host defense, which would then allow us to highlight the rationale use of autologous stem cells and their biochemical and immunological ability to reset the subverted immune responses. Recently, scientists have highlighted their use in the field of immune-therapy, establishing the possibilities of using them outside the conventional protocol with the advancement in manipulating these cells in such a way that specific body activity can be restored. This paper describes the remarkable SCs profile and discusses some ideas regarding their promising use in vivo.

Expediting Molecular Translational Approach of Mesenchymal Stem Cells in COVID-19 Treatment.

Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 with severe respiratory failure and organ damage that later appeared as a pandemic disease. Worldwide, people's mental and physical health and socioeconomic have been affected. Currently, with no promising treatment for COVID-19, the existing anti-viral drugs and vaccines are the only hope to boost the host immune system to reduce morbidity and mortality rate. Unfortunately, several reports show that people who are partially or fully vaccinated are still susceptible to COVID-19 infection. Evidence suggests that COVID-19 immunopathology may include dysregulation of macrophages and monocytes, reduced type 1 interferons (IFN-1), and enhanced cytokine storm that results in hypersecretion of proinflammatory cytokines, capillary leak syndrome, intravascular coagulation, and acute respiratory distress syndrome (ARDS) ultimately leading to the worsening of patient's condition and death in most cases. The recent use of cell-based therapies such as mesenchymal stem cells (MSCs) for critically ill COVID-19 patients has been authorized by the Food and Drug Administration (FDA) to alleviate cytokine release syndrome. It protects the alveolar epithelial cells by promoting immunomodulatory action and secreting therapeutic exosomes to improve lung function and attenuate respiratory failure. As a result, multiple clinical trials have been registered using MSCs that aim to use various cell sources, and dosages to promote safety and efficacy against COVID-19 infection. In this review, the possibility of using MSCs in COVID-19 treatment and its associated challenges in their use have been briefly discussed.

Mesenchymal Stem Cells: A Potent Cell Source for COVID-19

Coronaviruses are enveloped positive-stranded RNA viruses that cause mild to acute respiratory illness. Coronaviruses can merge envelope proteins with the host cell membranes and de-liver their genetic material. Coronavirus disease 2019 (COVID-19) is the seventh coronavirus clos-est to the severe acute respiratory syndrome (SARS) in bats that infects humans. COVID-19 at-tacks the respiratory system and stimulates the host inflammatory responses, promotes the recruit-ment of immune cells, and enhances angiotensin-converting enzyme 2 (ACE2) activities. Patients with confirmed COVID-19 have experienced fever, dry cough, headache, dyspnea, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. Inflammation is a common and important factor in the pathogenesis of COVID-19. In recent years, stem cell-based therapies represent a promising therapeutic option against various diseases. Mesenchymal stem cells (MSCs) are multipotent stem cells that can self-renew and differentiate into various tissues of mesodermal ori-gin. MSCs can be derived from bone marrow, adipose tissue, and umbilical cord blood. MSCs, with their unique immunomodulatory properties, represent a promising therapeutic alternative against diseases associated with inflammation. Several previous studies have shown that MSCs with a strong safety profile can improve the treatment of patients with COVID-19. The information in this review provides a summary of the prevention and diagnosis of COVID-19. Also, we focus on the current clinical application of MSCs for treatments of patients with COVID-19.Copyright © 2021 Bentham Science Publishers.

The use of mesenchymal stem cells in the treatment of severe forms of new coronavirus infection COVID-19: a prospective observational study

INTRODUCTION: One of the promising treatments for COVID-19 aimed at correcting the immune response and re-ducing the level of pro-inflammatory cytokines is the use of mesenchymal stem cells (MSCs). There is evidence that MSCs, due to various mechanisms, are able to suppress the cytokine storm in patients with COVID-19. Thus, the use of MSCs can contribute to the suppression of inflammation and the regulation of immune homeostasis in patients with severe COVID-19. OBJECTIVE: Evaluation of the ef-fect of mesenchymal stem cell (MSC) therapy on the course of severe forms of novel coronavirus infection, accompanied by "cytokine storm”. MATERIALS AND METHODS: A prospective single-center study included 39 patients treated for coronavirus infection on the basis of the intensive care unit and, after randomization, randomly divided into control (n = 16) and study groups (n = 23). An assessment of clinical, laboratory parameters in both groups and a cytokine profile in the study group was carried out. Outcomes were compared, the incidence of complications and clinical and laboratory parameters in both groups, and the cytokine profile in the study group. RESULTS: The use of MSCs in patients with severe forms of COVID-19 affected the outcomes of the disease, the duration of stay on mechanical ventilation, the course of acute respiratory distress syndrome (ARDS) (an increase in the oxygenation index in patients of the study group by 5, 7 days from administration in comparison with the control group). CONCLUSIONS: In patients treated with MSCs, there was a significant decrease in a number of pro-inflam-matory cytokines. © 2023, Practical Medicine Publishing House LLC. All rights reserved.

The use of mesenchymal stem cells in the treatment of severe forms of new coronavirus infection COVID-19: a prospective observational study

INTRODUCTION: One of the promising treatments for COVID-19 aimed at correcting the immune response and re-ducing the level of pro-inflammatory cytokines is the use of mesenchymal stem cells (MSCs). There is evidence that MSCs, due to various mechanisms, are able to suppress the cytokine storm in patients with COVID-19. Thus, the use of MSCs can contribute to the suppression of inflammation and the regulation of immune homeostasis in patients with severe COVID-19. OBJECTIVE: Evaluation of the ef-fect of mesenchymal stem cell (MSC) therapy on the course of severe forms of novel coronavirus infection, accompanied by "cytokine storm”. MATERIALS AND METHODS: A prospective single-center study included 39 patients treated for coronavirus infection on the basis of the intensive care unit and, after randomization, randomly divided into control (n = 16) and study groups (n = 23). An assessment of clinical, laboratory parameters in both groups and a cytokine profile in the study group was carried out. Outcomes were compared, the incidence of complications and clinical and laboratory parameters in both groups, and the cytokine profile in the study group. RESULTS: The use of MSCs in patients with severe forms of COVID-19 affected the outcomes of the disease, the duration of stay on mechanical ventilation, the course of acute respiratory distress syndrome (ARDS) (an increase in the oxygenation index in patients of the study group by 5, 7 days from administration in comparison with the control group). CONCLUSIONS: In patients treated with MSCs, there was a significant decrease in a number of pro-inflam-matory cytokines. © 2023, Practical Medicine Publishing House LLC. All rights reserved.

The Emergence of Novel Coronavirus Disease, Global Treatment Update and its Containment Strategies in Overpopulated Countries: A Review

The ongoing pandemic of the novel coronavirus SARS-CoV-2 (COVID-19) has created a major challenge for the public health worldwide. The reported cases indicate that the outbreak is more widespread than initially assumed. Around 18 million people have been infected with 689,000 reported deaths (August 2020;the number is increasing daily);with a high mutation rate, this virus poses an even more serious threat worldwide. The actual source of COVID-19 is still un-clear;even if the initial reports link it to the Chinese seafood wet market in Wuhan, other animals such as birds, snakes, and many small mammals including bats are also linked with this novel coro-navirus. The structure of the COVID-19 shows distinctive proteins among which spike proteins have a pivotal role in host cell attachment and virus-cell membrane fusion in order to facilitate virus infection. Currently, no specific antiviral treatment or vaccine is available. Various drug can-didates, including SARS-CoV and MERS-CoV protease inhibitors, neuraminidase inhibitors, RNA synthesis inhibitors, ACE2 inhibitors and lungs supportive therapy, are under trials. Cell-based therapy also appeared with remarkable treatment possibilities. In this article, we endeavored to succinctly cover the current and available treatment options, including pharmaceuticals, cell-based therapy, and traditional medicine. We also focused on the extent of damages by this novel coron-avirus in India, Pakistan, and Bangladesh;the strategies adopted and the research activities initiat-ed so far by these densely populated countries (neighboring China) are explained in this review.Copyright © 2021 Bentham Science Publishers.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis.

The objective of this study was to assess whether mesenchymal stem cells (MSCs) therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang, and CNKI was performed from December 1, 2019 to December 25, 2022. The primary outcome was all-cause mortality. Trial sequential analysis (TSA) was conducted in this meta analysis. Besides, subgroup analysis and meta-regression was performed using a random-effects model to find the potential sources of heterogeneity. Seventeen randomized controlled trials (RCTs) involving a total of 1073 patients with COVID-19 were included in this study. Compared with the control group, patients in the MSCs groups were associated with significantly reduced all-cause mortality (MSCs 18.4% vs. control 25.5%; risk ratio [RR] 0.73; 95% confidence interval [CI] 0.59-0.90; p = 0.004; I² = 0%). For all secondary outcomes, there wasn't significant improvement in the experimental group versus the control group regarding symptom remission rate (53.2%, 201/378 vs. 46.5%, 164/353; RR 1.15; 95% CI 1.00-1.32; p = 0.05; I² = 43%), but the pooled analysis revealed significant differences between the groups in length of hospital stay (MD: -3.82, 95% CI: -5.87 to -1.77; p = 0.0003, I2 = 0%), requirement of invasive mechanical ventilation (RR 0.52; 95% CI 0.33-0.82; p = 0.005; I2 = 0%) and post-CRP level (MD: -31.61; 95% CI -46.74 to -16.49; p < 0.0001). Moreover, regarding the incidence of adverse events (AEs) (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and serious adverse events (sAEs) (RR 0.87; 95% CI 0.40-1.92; p = 0.73; I² = 39%), no significant differences were observed between MSCs and control groups. The TSA analysis showed that the result of all-cause mortality might be false-positive result. Based on the pooled results in this study, compared with standard treatment, MSCs therapy may reduce all-cause mortality of patients with COVID-19 with no increase risk of AEs and sAEs, but may not improve symptom remission rate. Further more high-quality and large-sample RCTs should be performed to confirm these findings.

Current status in cellular-based therapies for prevention and treatment of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) outbreaks that resulted in a catastrophic threat to global health, with more than 500 million cases detected and 5.5 million deaths worldwide. Patients with a COVID-19 infection presented with clinical manifestations ranging from asymptomatic to severe symptoms, resulting in acute lung injury, acute respiratory distress syndrome, and even death. Immune dysregulation through delayed innate immune response or impairment of the adaptive immune response is the key contributor to the pathophysiology of COVID-19 and SARS-CoV-2-induced cytokine storm. Symptomatic and supportive therapy is the fundamental strategy in treating COVID-19 infection, including antivirals, steroid-based therapies, and cell-based immunotherapies. Various studies reported substantial effects of immune-based therapies for patients with COVID-19 to modulate the over-activated immune system while simultaneously refining the body's ability to destroy the virus. However, challenges may arise from the complexity of the disease through the genetic variance of the virus itself and patient heterogeneity, causing increased transmissibility and heightened immune system evasion that rapidly change the intervention and prevention measures for SARS-CoV-2. Cell-based therapy, utilizing stem cells, dendritic cells, natural killer cells, and T cells, among others, are being extensively explored as other potential immunological approaches for preventing and treating SARS-CoV-2-affected patients the similar process was effectively proven in SARS-CoV-1 and MERS-CoV infections. This review provides detailed insights into the innate and adaptive immune response-mediated cell-based immunotherapies in COVID-19 patients. The immune response linking towards engineered autologous or allogenic immune cells for either treatment or preventive therapies is subsequently highlighted in an individual study or in combination with several existing treatments. Up-to-date data on completed and ongoing clinical trials of cell-based agents for preventing or treating COVID-19 are also outlined to provide a guide that can help in treatment decisions and future trials.

Use of mesenchymal stem cell therapy in COVID-19 related strokes.

Coronavirus disease 2019 (COVID-19) has affected a broad demographics, eliciting a more significant effect on specific groups such as males, African Americans, and Hispanic minorities. Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies. However, immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19. Mesenchymal stem cell therapy offers regenerative, anti-inflammatory, and immunomodulatory properties that can speed up the recovery from COVID-19. Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from strokes, as COVID-19 increases the risk of strokes due to increased cytokines and clotting factors. Most stroke cases that occur in COVID-19 patients are ischemic strokes. Therefore, with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes, COVID-19-induced stroke patients might benefit from dual-ended treatment. The objective of this review was to discuss COVID-19 and stroke incidence and the available treatment options.

Challenges and strategies: Scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy.

Exosomes are small membrane vesicles secreted by most cell types, and widely exist in cell supernatants and various body fluids. They can transmit numerous bioactive elements, such as proteins, nucleic acids, and lipids, to affect the gene expression and function of recipient cells. Mesenchymal stem cells (MSCs) have been confirmed to be a potentially promising therapy for tissue repair and regeneration. Accumulating studies demonstrated that the predominant regenerative paradigm of MSCs transplantation was the paracrine effect but not the differentiation effect. Exosomes secreted by MSCs also showed similar therapeutic effects as their parent cells and were considered to be used for cell-free regenerative medicine. However, the inefficient and limited production has hampered their development for clinical translation. In this review, we summarize potential methods to efficiently promote the yield of exosomes. We mainly focus on engineering the process of exosome biogenesis and secretion, altering the cell culture conditions, cell expansion through 3D dynamic culture and the isolation of exosomes. In addition, we also discuss the application of MSCs-derived exosomes as therapeutics in disease treatment.

Three-Dimensional Bioprinting of an In Vitro Lung Model.

In December 2019, COVID-19 emerged in China, and in January 2020, the World Health Organization declared a state of international emergency. Within this context, there is a significant search for new drugs to fight the disease and a need for in vitro models for preclinical drug tests. This study aims to develop a 3D lung model. For the execution, Wharton's jelly mesenchymal stem cells (WJ-MSC) were isolated and characterized through flow cytometry and trilineage differentiation. For pulmonary differentiation, the cells were seeded in plates coated with natural functional biopolymer matrix as membrane until spheroid formation, and then the spheroids were cultured with differentiation inductors. The differentiated cells were characterized using immunocytochemistry and RT-PCR, confirming the presence of alveolar type I and II, ciliated, and goblet cells. Then, 3D bioprinting was performed with a sodium alginate and gelatin bioink in an extrusion-based 3D printer. The 3D structure was analyzed, confirming cell viability with a live/dead assay and the expression of lung markers with immunocytochemistry. The results showed that the differentiation of WJ-MSC into lung cells was successful, as well as the bioprinting of these cells in a 3D structure, a promising alternative for in vitro drug testing.

Treatment of Acute Respiratory Distress Syndrome Caused by COVID-19 with Human Umbilical Cord Mesenchymal Stem Cells.

This study aimed to identify the impact of mesenchymal stem cell transplantation on the safety and clinical outcomes of patients with severe COVID-19. This research focused on how lung functional status, miRNA, and cytokine levels changed following mesenchymal stem cell transplantation in patients with severe COVID-19 pneumonia and their correlation with fibrotic changes in the lung. This study involved 15 patients following conventional anti-viral treatment (Control group) and 13 patients after three consecutive doses of combined treatment with MSC transplantation (MCS group). ELISA was used to measure cytokine levels, real-time qPCR for miRNA expression, and lung computed tomography (CT) imaging to grade fibrosis. Data were collected on the day of patient admission (day 0) and on the 7th, 14th, and 28th days of follow-up. A lung CT assay was performed on weeks 2, 8, 24, and 48 after the beginning of hospitalization. The relationship between levels of biomarkers in peripheral blood and lung function parameters was investigated using correlation analysis. We confirmed that triple MSC transplantation in individuals with severe COVID-19 was safe and did not cause severe adverse reactions. The total score of lung CT between patients from the Control and MSC groups did not differ significantly on weeks 2, 8, and 24 after the beginning of hospitalization. However, on week 48, the CT total score was 12 times lower in patients in the MSC group (p ≤ 0.05) compared to the Control group. In the MSC group, this parameter gradually decreased from week 2 to week 48 of observation, whereas in the Control group, a significant drop was observed up to week 24 and remained unchanged afterward. In our study, MSC therapy improved lymphocyte recovery. The percentage of banded neutrophils in the MSC group was significantly lower in comparison with control patients on day 14. Inflammatory markers such as ESR and CRP decreased more rapidly in the MSC group in comparison to the Control group. The plasma levels of surfactant D, a marker of alveocyte type II damage, decreased after MSC transplantation for four weeks in contrast to patients in the Control group, in whom slight elevations were observed. We first showed that MSC transplantation in severe COVID-19 patients led to the elevation of the plasma levels of IP-10, MIP-1α, G-CSF, and IL-10. However, the plasma levels of inflammatory markers such as IL-6, MCP-1, and RAGE did not differ between groups. MSC transplantation had no impact on the relative expression levels of miR-146a, miR-27a, miR-126, miR-221, miR-21, miR-133, miR-92a-3p, miR-124, and miR-424. In vitro, UC-MSC exhibited an immunomodulatory impact on PBMC, increasing neutrophil activation, phagocytosis, and leukocyte movement, activating early T cell markers, and decreasing effector and senescent effector T cell maturation.