Stem cells used in infectious diseases like pneumonia, respiratory infections and Covid-19: A study based on doctor's opinion

Worldwide, infectious diseases have contributed significantly to morbidity and mortality;among the leading causes of death are pneumonia, respiratory infections and Covid-19. Stem cell therapy will be used to treat virus-infected patients in an effective and safe manner. A cross-sectional questionnaire was used to collect data from doctors. Most doctors are aware of the applications of stem cells, but they do not confirm their usage because clinical trials are ongoing. Instead, they show support for using stem cells to treat patients. Stem cells have been hoping to help repair damaged tissues in the respiratory system to promote faster recovery. Stem Cells are being studied in current clinical trials for their efficacy and safety in virus severe pneumonia and respiratory infections. The doctors suggested that stem cells have been used in infectious diseases to improve their health.Copyright © 2023 Health Biotechnology And Biopharma. All rights reserved.

Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation.

We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.

Magnetic Nanostructures and Stem Cells for Regenerative Medicine, Application in Liver Diseases.

The term "liver disease" refers to any hepatic condition that leads to tissue damage or altered hepatic function and can be induced by virus infections, autoimmunity, inherited genetic mutations, high consumption of alcohol or drugs, fat accumulation, and cancer. Some types of liver diseases are becoming more frequent worldwide. This can be related to increasing rates of obesity in developed countries, diet changes, higher alcohol intake, and even the coronavirus disease 2019 (COVID-19) pandemic was associated with increased liver disease-related deaths. Although the liver can regenerate, in cases of chronic damage or extensive fibrosis, the recovery of tissue mass is impossible, and a liver transplant is indicated. Because of reduced organ availability, it is necessary to search for alternative bioengineered solutions aiming for a cure or increased life expectancy while a transplant is not possible. Therefore, several groups were studying the possibility of stem cells transplantation as a therapeutic alternative since it is a promising strategy in regenerative medicine for treating various diseases. At the same time, nanotechnological advances can contribute to specifically targeting transplanted cells to injured sites using magnetic nanoparticles. In this review, we summarize multiple magnetic nanostructure-based strategies that are promising for treating liver diseases.

The evolving regulatory landscape in regenerative medicine.

Regenerative medicine as a field has emerged as a new component of modern medicine and medical research that encompasses a wide range of products including cellular and acellular therapies. As this new field emerged, regulatory agencies like the Food and Drug Administration (FDA) rapidly adapted existing regulatory frameworks to address the transplantation, gene therapy, cell-based therapeutics, and acellular biologics that fall under the broader regenerative medicine umbrella. Where it has not been possible to modify existing regulation and processes, entirely new frameworks have been generated with the intention of providing flexible, forward-facing systems to regulate this rapidly growing field. This review discusses the current state of FDA regulatory affairs in the context of stem cells and extracellular vesicles by highlighting gaps in the current regulatory system and then discussing where regulatory science in regenerative medicine may be headed based on these gaps and the FDA's historical ability to deal with emerging fields. Lastly, we utilize case studies in stem cell and acellular based treatments to demonstrate how regulatory science has evolved in regenerative medicine and highlight the ongoing clinical efforts and challenges of these therapies.

Cell Therapy: cGMP Facilities and Manufacturing: Second Edition

This new edition presents a fully-updated and expanded look at current Good Manufacturing Practice (cGMP) for cell therapy products. It provides a complete discussion of facility design and operation including details specific to cord blood banking, cell processing, vector production and qualification of a new facility. Several chapters cover facility infrastructure including cleaning and maintenance, vendor qualification, writing a Standard Operating Procedure, staff training, and process validation. The detailed and invaluable product information covers topics like labelling, release and administration, transportation and shipment, et al. Further chapters cover relevant topics like writing and maintaining investigational new drug applications, support opportunities in North America and the European Union, commercial cell processing and quality testing services, and financial considerations for academic GMP facilities. A chapter on future directions rounds out Cell Therapy: cGMP Facilities and Manufacturing making it essential reading for any cell therapy professional involved in the development, use, or management of this type of facility. © Springer Nature Switzerland AG 2009, 2022, Corrected Publication 2022.

Application prospects of organoids in organ transplantation

In recent years, organoid technology has become one of the major technological breakthroughs in biomedical field. As miniature organs constructed by three-dimensional culture of tissue stem cells in vitro, organoids are highly consistent with the source tissues in terms of tissue structures, cell types and functions, which serve as an ideal model for biomedical basic research, drug research and development and clinical precision medicine, and show important potential value in regenerative medicine. Organ transplantation is one of the most effective approaches to treat organ failure. However, the source of donor organs is currently limited, which could not meet the patients' needs. Identifying suitable graft substitutes is the key to breaking through the predicament. Organoids could be derived from the autologous tissues of patients. Multiple studies have demonstrated that organoids possess potent transplantation and repairing capabilities and may effectively avert the risk of immune rejection and tumorigenicity, etc. In this article, the development process and main application directions of organoid technology were summarized, and the application prospect and challenges of organoids in organ transplantation were reviewed and predicted.Copyright © 2022 Journal of Zhongshan University. All right reserved.

The preclinical and clinical progress of cell sheet engineering in regenerative medicine.

Cell therapy is an accessible method for curing damaged organs or tissues. Yet, this approach is limited by the delivery efficiency of cell suspension injection. Over recent years, biological scaffolds have emerged as carriers of delivering therapeutic cells to the target sites. Although they can be regarded as revolutionary research output and promote the development of tissue engineering, the defect of biological scaffolds in repairing cell-dense tissues is apparent. Cell sheet engineering (CSE) is a novel technique that supports enzyme-free cell detachment in the shape of a sheet-like structure. Compared with the traditional method of enzymatic digestion, products harvested by this technique retain extracellular matrix (ECM) secreted by cells as well as cell-matrix and intercellular junctions established during in vitro culture. Herein, we discussed the current status and recent progress of CSE in basic research and clinical application by reviewing relevant articles that have been published, hoping to provide a reference for the development of CSE in the field of stem cells and regenerative medicine.

Role of MSC-derived small extracellular vesicles in tissue repair and regeneration.

Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and repair, secreting vesicles to the extracellular environment. Isolated exosomes were shown to affect angiogenesis, immunomodulation and tissue regeneration. Numerous efforts have been dedicated to describe the mechanism of action of these extracellular vesicles (EVs) and guarantee their safety, since the final aim is their therapeutic application in the clinic. The major advantage of applying MSC-derived EVs is their low or inexistent immunogenicity, prompting their use as drug delivery or therapeutic agents, as well as wound healing, different cancer types, and inflammatory processes in the neurological and cardiovascular systems. MSC-derived EVs display no vascular obstruction effects or apparent adverse effects. Their nano-size ensures their passage through the blood-brain barrier, demonstrating no cytotoxic or immunogenic effects. Several in vitro tests have been conducted with EVs obtained from different sources to understand their biology, molecular content, signaling pathways, and mechanisms of action. Application of EVs to human therapies has recently become a reality, with clinical trials being conducted to treat Alzheimer's disease, retina degeneration, and COVID-19 patients. Herein, we describe and compare the different extracellular vesicles isolation methods and therapeutic applications regarding the tissue repair and regeneration process, presenting the latest clinical trial reports.

Viruses as biomaterials

Viruses lacking the capacity to infect mammals exhibit minimal toxicity, good biocompatibility, and well-defined structures. As self-organized biomolecular assemblies, they can be produced from standard biological techniques on a large scale at a low cost. Genetic, chemical, self-assembly, and mineralization techniques have been applied to allow them to display functional peptides or proteins, encapsulate therapeutic drugs and genes, assemble with other materials, and be conjugated with bioactive molecules, enabling them to bear different biochemical properties. So far, a variety of viruses (infecting bacteria, plants, or animals), as well as their particle variants, have been used as biomaterials to advance human disease prevention, diagnosis, and treatment. Specifically, the virus-based biomaterials can serve as multifunctional nanocarriers for targeted therapy, antimicrobial agents for infectious disease treatment, hierarchically structured scaffolds for guiding cellular differentiation and promoting tissue regeneration, versatile platforms for ultrasensitive disease detection, tissue-targeting probes for precision bioimaging, and effective vaccines and immunotherapeutic agents for tackling challenging diseases. This review provides an in-depth discussion of these exciting applications. It also gives an overview of the viruses from materials science perspectives and attempts to correlate the structures, properties, processing, and performance of virus-based biomaterials. It describes the use of virus-based biomaterials for preventing and treating COVID-19 and discusses the challenges and future directions of virus-based biomaterials research. It summarizes the progressive clinical trials of using viruses in humans. With the impressive progress made in the exciting field of virus-based biomaterials, it is clear that viruses are playing key roles in advancing important areas in biomedicine such as early detection and prevention, drug delivery, infectious disease treatment, cancer therapy, nanomedicine, and regenerative medicine. [ FROM AUTHOR] Copyright of Materials Science & Engineering: R is the property of Elsevier B.V. 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.)

Nanotechnology and stem cell therapy for combating COVID-19

After the initial occurrence in Wuhan, Hubei Province, China, at the end of the year 2019, Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has wreaked havoc on livelihoods and health worldwide. By the end of June 2021, more than 3 million deaths and a total of more than 179 million positive cases have been registered, and the numbers are steadily climbing (https://covid19.who.int/). The principal life-threatening manifestations of COVID-19 illness are caused by the dysregulated immune system and inflammatory response triggered by a surge of cytokines known as cytokine storm. This makes the lower respiratory tract more susceptible to infection resulting in acute lung injury/acute respiratory distress syndrome intermittently resulting in the death of the patient. The range of medicinal therapy available to treat COVID-19 is continuously expanding and includes both the Food and Drug Administration (FDA)-approved drugs as well as medications approved for emergency use by the FDA. The world has greeted extremely encouraging and long-awaited COVID-19 vaccination. A total of 2,624,733,776 vaccine doses have been globally administered (https://covid19.who.int/) by June 23, 2021. Even though prevention therapy in form of vaccinations is currently accessible to some, logistics and limited supplies will make it months before the entire world gets vaccinated. Even after more than one and a half years of this global threat, there are no specific therapeutics to treat this viral infection with only a few repurposed drugs authorized to treat COVID-19. Hence, multiple treatment strategies to reduce the severity of COVID-19 impact on patients must be explored. © 2023 Elsevier Inc. All rights reserved.

Viruses as biomaterials

Viruses lacking the capacity to infect mammals exhibit minimal toxicity, good biocompatibility, and well-defined structures. As self-organized biomolecular assemblies, they can be produced from standard biological techniques on a large scale at a low cost. Genetic, chemical, self-assembly, and mineralization techniques have been applied to allow them to display functional peptides or proteins, encapsulate therapeutic drugs and genes, assemble with other materials, and be conjugated with bioactive molecules, enabling them to bear different biochemical properties. So far, a variety of viruses (infecting bacteria, plants, or animals), as well as their particle variants, have been used as biomaterials to advance human disease prevention, diagnosis, and treatment. Specifically, the virus-based biomaterials can serve as multifunctional nanocarriers for targeted therapy, antimicrobial agents for infectious disease treatment, hierarchically structured scaffolds for guiding cellular differentiation and promoting tissue regeneration, versatile platforms for ultrasensitive disease detection, tissue-targeting probes for precision bioimaging, and effective vaccines and immunotherapeutic agents for tackling challenging diseases. This review provides an in-depth discussion of these exciting applications. It also gives an overview of the viruses from materials science perspectives and attempts to correlate the structures, properties, processing, and performance of virus-based biomaterials. It describes the use of virus-based biomaterials for preventing and treating COVID-19 and discusses the challenges and future directions of virus-based biomaterials research. It summarizes the progressive clinical trials of using viruses in humans. With the impressive progress made in the exciting field of virus-based biomaterials, it is clear that viruses are playing key roles in advancing important areas in biomedicine such as early detection and prevention, drug delivery, infectious disease treatment, cancer therapy, nanomedicine, and regenerative medicine. © 2023 Elsevier B.V.

Industry updates from the field of stem cell research and regenerative medicine in September 2020.

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions in September 2020.

Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives.

In the last few decades, the practical use of stem cells (SCs) in the clinic has attracted significant attention in the regenerative medicine due to the ability of these cells to proliferate and differentiate into other cell types. However, recent findings have demonstrated that the therapeutic capacity of SCs may also be mediated by their ability to secrete biologically active factors, including extracellular vesicles (EVs). Such submicron circular membrane-enveloped vesicles may be released from the cell surface and harbour bioactive cargo in the form of proteins, lipids, mRNA, miRNA, and other regulatory factors. Notably, growing evidence has indicated that EVs may transfer their bioactive content into recipient cells and greatly modulate their functional fate. Thus, they have been recently envisioned as a new class of paracrine factors in cell-to-cell communication. Importantly, EVs may modulate the activity of immune system, playing an important role in the regulation of inflammation, exhibiting broad spectrum of the immunomodulatory activity that promotes the transition from pro-inflammatory to pro-regenerative environment in the site of tissue injury. Consequently, growing interest is placed on attempts to utilize EVs in clinical applications of inflammatory-related dysfunctions as potential next-generation therapeutic factors, alternative to cell-based approaches. In this review we will discuss the current knowledge on the biological properties of SC-derived EVs, with special focus on their role in the regulation of inflammatory response. We will also address recent findings on the immunomodulatory and pro-regenerative activity of EVs in several disease models, including in vitro and in vivo preclinical, as well as clinical studies. Finally, we will highlight the current perspectives and future challenges of emerging EV-based therapeutic strategies of inflammation-related diseases treatment.

Insights into organoid-based modeling of COVID-19 pathology.

Since December 2019, various types of strategies have been applied due to the emergent need to investigate the biology and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to discover a functional treatment. Different disease modeling systems, such as mini-organ technology, have been used to improve our understanding of SARS-CoV-2 physiology and pathology. During the past 2 years, regenerative medicine research has shown the supportive role of organoid modeling in controlling coronavirus disease 2019 (COVID-19) through optimal drug and therapeutic approach improvement. Here, we overview some efforts that have been made to study SARS-CoV-2 by mimicking COVID-19 using stem cells. In addition, we summarize a perspective of drug development in COVID-19 treatment via organoid-based studies.

Bone Marrow Mesenchymal Stem Cells Expanded Inside the Nichoid Micro-Scaffold: a Focus on Anti-Inflammatory Response.

Purpose: Mesenchymal stem cells (MSCs) represent a promising source for stem cell therapies in numerous diseases, including pediatric respiratory system diseases. Characterized by low immunogenicity, high anti-inflammatory, and immunoregulatory features, MSCs demonstrated an excellent therapeutic profile in numerous in vitro and preclinical models. MSCs reside in a specialized physiologic microenvironment, characterized by a unique combination of biophysical, biochemical, and cellular properties. The exploitation of the 3D micro-scaffold Nichoid, which simulates the native niche, enhanced the anti-inflammatory potential of stem cells through mechanical stimulation only, overcoming the limitation of biochemical and xenogenic growth factors application. Materials and Methods: In this work, we expanded pediatric bone marrow MSCs (BM-MSCs) inside the Nichoid and performed a complete cellular characterization with different approaches including viability assays, immunofluorescence analyses, RNA sequencing, and gene expression analysis. Results: We demonstrated that BM-MSCs inside the scaffold remain in a stem cell quiescent state mimicking the condition of the in vivo environment. Moreover, the gene expression profile of these cells shows a significant up-regulation of genes involved in immune response when compared with the flat control. Conclusion: The significant changes in the expression profile of anti-inflammatory genes could potentiate the therapeutic effect of BM-MSCs, encouraging the possible clinical translation for the treatment of pediatric congenital and acquired pulmonary disorders, including post-COVID lung manifestations. Lay Summary: Regenerative medicine is the research field integrating medicine, biology, and biomedical engineering. In this context, stem cells, which are a fundamental cell source able to regenerate tissues and restore damage in the body, are the key component for a regenerative therapeutic approach. When expanded outside the body, stem cells tend to differentiate spontaneously and lose regenerative potential due to external stimuli. For this reason, we exploit the scaffold named Nichoid, which mimics the in vivo cell niche architecture. In this scaffold, mesenchymal stem cells "feel at home" due to the three-dimensional mechanical stimuli, and our findings could be considered as an innovative culture system for the in vitro expansion of stem cells for clinical translation. Future Perspective: The increasing demand of safe and effective cell therapies projects our findings toward the possibility of improving cell therapies based on the use of BM-MSCs, particularly for their clinical translation in lung diseases.

Electrophysiological approaches to study cystic fibrosis transmembrane conductance regulator function from human induced pluripotent stem cell-derived airway basal cells

Background: Induced pluripotent stem cells (iPSCs), self-renewable and reprogrammed from somatic cells using different transcription factors, are considered an ideal resource for regenerative medicine to replace diseased or damaged tissues. Airway basal cells not only serve as precursors for secretory and multiciliated cells, but also contribute to maintenance and regeneration of the airway epithelial barrier. Recently, it was reported that induced basal cells (iBCs) from human iPSCs recapitulate molecular and functional features from human iPSCs of airway basal cells, including selfrenewal and multilineage differentiation [1]. iBCs as in vitro model can be used in research on diseases affecting the airway, including COVID-19, influenza, asthma, and cystic fibrosis, although despite these advantages in generating iBCs, this is insufficient to support electrophysiological evidence. Our goal in this study is to define CFTR function in iPSCderived iBCs using electrophysiological methods. Method(s): An iPSC line containing dual reporter NKX2.1GFP and TP63tdTOMATO were used to generate iBCs according to a previously published protocol [1]). iBCs were differentiated into ciliated cells using air-liquid interface (ALI) culture. Short-circuit current measurements were taken on the cells cultured in ALI culture using an Ussing chamber using a previously described protocol [2]). To measure CFTR current using electrophysiological studies, fully differentiated monolayers on filters were dissociated into single cells, which were fixed onto a collagencoated cover glass using cytospin. Whole-cell patch-clamp recordingswere performed according to a previous published protocol [3]. Result(s): We generated proximal airway iBCs from iPSCs with the dualfluorescent reporter system of green fluorescent protein (marks lung progenitors) and tdTomato (marks subsequent airway progenitor) (Figure 1a). These cells on ALI culture demonstrated CFTR function using short-circuit current measurements (Figure 1b). We also measured CFTRdependent currents in iPSC-airway basal cells using whole-cell patchclamp recording (Figure 2). Conclusion(s): We identified CFTR function in electrophysiological experiments using airway iBCs in vitro from iPSCs. Therefore, our study helps advance the field of regenerative medicine, benefiting airway and lung diseases. This may ultimately allowfor development of individual, diseasespecific airway basal stem cells, leading to drug development and a platform on which targeted drug approaches can be tested. Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice.

Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases. The aim of this review was to systematize scientific data on the applications of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in the combined treatment of infectious diseases. Application of MSCs and MSC-EVs in the treatment of infectious diseases has immunomodulatory, anti-inflammatory, and antibacterial effects, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases, particularly in combination with antiviral drugs. Employment of MSC-derived EVs represents a more promising strategy for cell-free treatment, demonstrating a high therapeutic potential in preclinical studies.

Forthcoming complications in recovered COVID-19 patients with COPD and asthma; possible therapeutic opportunities.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been growing swiftly worldwide. Patients with background chronic pulmonary inflammations such as asthma or chronic obstructive pulmonary diseases (COPD) are likely to be infected with this virus. Of note, there is an argument that COVID-19 can remain with serious complications like fibrosis or other pathological changes in the pulmonary tissue of patients with chronic diseases. Along with conventional medications, regenerative medicine, and cell-based therapy could be alternative approaches to compensate for organ loss or restore injured sites using different stem cell types. Owing to unique differentiation capacity and paracrine activity, these cells can accelerate the healing procedure. In this review article, we have tried to scrutinize different reports related to the harmful effects of SARS-CoV-2 on patients with asthma and COPD, as well as the possible therapeutic effects of stem cells in the alleviation of post-COVID-19 complications. Video abstract.

Contribution of Trp63CreERT2-labeled cells to alveolar regeneration is independent of tuft cells.

Viral infection often causes severe damage to the lungs, leading to the appearance of ectopic basal cells (EBCs) and tuft cells in the lung parenchyma. Thus far, the roles of these ectopic epithelial cells in alveolar regeneration remain controversial. Here, we confirm that the ectopic tuft cells are originated from EBCs in mouse models and COVID-19 lungs. The differentiation of tuft cells from EBCs is promoted by Wnt inhibition while suppressed by Notch inhibition. Although progenitor functions have been suggested in other organs, pulmonary tuft cells don't proliferate or give rise to other cell lineages. Consistent with previous reports, Trp63CreERT2 and KRT5-CreERT2-labeled ectopic EBCs do not exhibit alveolar regeneration potential. Intriguingly, when tamoxifen was administrated post-viral infection, Trp63CreERT2 but not KRT5-CreERT2 labels islands of alveolar epithelial cells that are negative for EBC biomarkers. Furthermore, germline deletion of Trpm5 significantly increases the contribution of Trp63CreERT2-labeled cells to the alveolar epithelium. Although Trpm5 is known to regulate tuft cell development, complete ablation of tuft cell production fails to improve alveolar regeneration in Pou2f3-/- mice, implying that Trpm5 promotes alveolar epithelial regeneration through a mechanism independent of tuft cells.