MicroRNAs: The Master Regulators of the Breast Cancer Tumor Microenvironment

Breast cancer is the most commonly diagnosed cancer globally and is among the leading causes of cancer deaths worldwide. Breast cancer mortality rates are increasing due to delays in diagnosis, prognosis, and treatment caused by the coronavirus disease 2019 (COVID-19) pandemic. Identification and validation of blood-based breast cancer biomarkers for early detection is a top priority worldwide. MicroRNAs (miRNAs) show the potential to serve as breast cancer biomarkers. miRNAs are small, endogenously produced RNAs that regulate growth and development. However, oncogenic miRNAs also play a major role in tumor growth and can alter the tumor microenvironment (TME) in favor of cancer metastasis. The TME represents a complex network of diverse cancerous and noncancerous cell types, secretory proteins, growth factors, and miRNAs. Complex interactions within the TME can promote cancer progression and metastasis via multiple mechanisms, including oxidative stress, hypoxia, angiogenesis, lymphangiogenesis, and cancer stem cell regulation. Here, we decipher the mechanisms of miRNA regulating the TME, intending to use that knowledge to identify miRNAs as therapeutic targets in breast cancer and use miRNAs as blood-based biomarkers. © Springer Nature Singapore Pte Ltd. 2022.

Application of MSCs therapy in COVID-19

The year 2019 ended with the official report of an unknown pneumonia outbreak in Wuhan, Hubei Province, China. Subsequently, this novel pneumonia was named COVID-19, which mainly attacks the respiratory system, causing severe damage. Although vaccination has relieved the stress of combating pandemics around the world after one year, there are still unknowns and challenges that come with hope. In this regard, stem cell therapy has been proposed as an effective approach to treating COVID-19. Mesenchymal stem cells (MSCs) can potentially be used as a hopeful tool in the cell-based therapy due to their ability to regenerate and regulate immune response. Although research and clinical results have shown encouraging achievement in patients who were treated with MSCs, drawbacks and challenges still exist in the face of new opportunities. This review aims to introduce the challenges of the COVID-19 vaccine and the possible clinical use of MSC-based therapy. Through analysis of COVID-19 and MSC-based therapy, the author aims to find the possibilities and feasibility of using MSCs to treat acute respiratory diseases, such as COVID. As a result, the author finds that MSC treatment is very practical, and it shows significant potential to treat COVID-19. © 2023 SPIE.

Frontrunners in the Latest Stem Cell Technology

Attracting investor attention In January 2022, the company was recognized as one of the top 25 BioTech start-ups (1). Since its conception, it has attracted USS86.9 million (€80.8 million) in series A and B funding from private equity investors, including Leonard Green and Partners, XAnge, AQUITI Gestion, BNP Paribas Developpement, and Bpifrance, as well as Bristol Myers Squibb, Aquitaine Science Transfer, and the European Commission (1). First-in-human trial expected in 2024 TreeFrog's lead programme targets Parkinson's disease via the generation of three-dimensional (3D) neurospheres which contain mature dopaminergic neurons. In 2022, TreeFrog awarded several Stem Cell SpaceShot grants to leading academic institutions including the University of Sheffield, UK;MCR Laboratory of Molecular Biology, 13 Dec 2022).

Frontrunners in Organ-on-a-Chip

Advances in tissue engineering, microfabrication, and biocompatible microfluidic chambers alongside the governmental (2) and regulatory (3) appetite to seek animal-free innovations in the drug development process has fuelled further interest and investment in this marketplace. According to market research, the global O°C market is forecast to be worth US$388 million (€354 million) by 2028 increasing from US$82 million (€75 million) in 2023, with a compound average growth of 36.4% from 2023 to 2028 (4). In March 2022, Lyon-based NETRI, attracted €8 million series A funding to help develop its novel high throughput (HT) compartmentalized microfluidic brain-on-a-chip and skin-on-a-chip technology for use by the pharma and cosmetic industry (15). Global Organ-onChip Market Size, Share, Trends, COVID-19 Impact and Growth Analysis ReportSegmented by Type (Heart-on-chip, Humanon-chip, Intestine-on-chip, Kidney-on-chip, Liver-on-chip and Lung-on-chip), Application and Region (North America, Europe, AsiaPacific, Latin America, Middle East and Africa)-Industry Forecast from 2023 to 2028.

A call for an integrated biology

The Song of the Cell tells the story of how we came to understand ourselves and other complex living organisms as mosaics of these atoms of life. There is the "dividing cell”, which takes us to the 2001 Nobel Prize in Physiology or Medicine that Nurse won, alongside Leland Hartwell and Tim Hunt, for elucidating the roles of cyclin and cyclin-dependent kinase proteins in regulating the cell cycle, and to the invention of reproductive in-vitro fertilisation by Patrick Steptoe and Robert Edwards during the 1970s. Quite what the "new human” of the subtitle refers to is never fully clear, but the ability to reprogramme cell states, as for example, in the method devised by stem-cell researcher Shinya Yamanaka to induce mature somatic cells back to pluripotency, might have the potential to grow organs in vitro, to regenerate tissues in vivo, and even to create synthetic embryo-like structures without the involvement of fertilisation. Mukherjee rightly admits that this view goes too far, but it might at least be understood as suggesting that trying to attack cancer at the genetic level is like hoping to stop traffic jams by fixing the faulty brakes of the car that caused the last one.

Porcine Deltacoronavirus Infection Disrupts the Intestinal Mucosal Barrier and Inhibits Intestinal Stem Cell Differentiation to Goblet Cells via the Notch Signaling Pathway.

Goblet cells and their secreted mucus are important elements of the intestinal mucosal barrier, which allows host cells to resist invasion by intestinal pathogens. Porcine deltacoronavirus (PDCoV) is an emerging swine enteric virus that causes severe diarrhea in pigs and causes large economic losses to pork producers worldwide. To date, the molecular mechanisms by which PDCoV regulates the function and differentiation of goblet cells and disrupts the intestinal mucosal barrier remain to be determined. Here, we report that in newborn piglets, PDCoV infection disrupts the intestinal barrier: specifically, there is intestinal villus atrophy, crypt depth increases, and tight junctions are disrupted. There is also a significant reduction in the number of goblet cells and the expression of MUC-2. In vitro, using intestinal monolayer organoids, we found that PDCoV infection activates the Notch signaling pathway, resulting in upregulated expression of HES-1 and downregulated expression of ATOH-1 and thereby inhibiting the differentiation of intestinal stem cells into goblet cells. Our study shows that PDCoV infection activates the Notch signaling pathway to inhibit the differentiation of goblet cells and their mucus secretion, resulting in disruption of the intestinal mucosal barrier. IMPORTANCE The intestinal mucosal barrier, mainly secreted by the intestinal goblet cells, is a crucial first line of defense against pathogenic microorganisms. PDCoV regulates the function and differentiation of goblet cells, thereby disrupting the mucosal barrier; however, the mechanism by which PDCoV disrupts the barrier is not known. Here, we report that in vivo, PDCoV infection decreases villus length, increases crypt depth, and disrupts tight junctions. Moreover, PDCoV activates the Notch signaling pathway, inhibiting goblet cell differentiation and mucus secretion in vivo and in vitro. Thus, our results provide a novel insight into the mechanism underlying intestinal mucosal barrier dysfunction caused by coronavirus infection.

COVID-19 disease treatment: pivotal challenges in the arena of umbilical cord-mesenchymal stem cells (UC-MSCs).

This century's first major epidemic of a new coronavirus illness (2019-nCoV) was a tremendous shock to the healthcare system. The onset of the pandemic has caused severe economic and health shortages. At this time, there are no viable treatments for COVID-19. Several clinical studies using cell-based therapies, such as umbilical cord mesenchymal stem cells, have showed promising results (UC-MSCs). UC-MSCs have been the focus of much study because to their potential as a treatment option for COVID-19 patients. Cytokine release syndrome, often called cytokine storm, increases the risk of morbidity and mortality from COVID-19. It has been established that UC-MSCs may suppress and control both the adaptive and innate immune responses by modulating the release of immunostimulatory cytokines. The purpose of this study is to assess and clarify the use of UC-MSCs for the treatment of ARDS caused by COVID-19.

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.

The sense of taste: Development, regeneration, and dysfunction.

Gustation or the sense of taste is a primary sense, which functions as a gatekeeper for substances that enter the body. Animals, including humans, ingest foods that contain appetitive taste stimuli, including those that have sweet, moderately salty and umami (glutamate) components, and tend to avoid bitter-tasting items, as many bitter compounds are toxic. Taste is mediated by clusters of heterogeneous taste receptors cells (TRCs) organized as taste buds on the tongue, and these convey taste information from the oral cavity to higher order brain centers via the gustatory sensory neurons of the seventh and ninth cranial ganglia. One remarkable aspect of taste is that taste perception is mostly uninterrupted throughout life yet TRCs within buds are constantly renewed; every 1-2 months all taste cells have been steadily replaced. In the past decades we have learned a substantial amount about the cellular and molecular regulation of taste bud cell renewal, and how taste buds are initially established during embryogenesis. Here I review more recent findings pertaining to taste development and regeneration, as well as discuss potential mechanisms underlying taste dysfunction that often occurs with disease or its treatment. This article is categorized under: Infectious Diseases > Stem Cells and Development Cancer > Stem Cells and Development Neurological Diseases > Stem Cells and Development.

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.

Rapid Generation of Pulmonary Organoids from Induced Pluripotent Stem Cells by Co-Culturing Endodermal and Mesodermal Progenitors for Pulmonary Disease Modelling.

Differentiation of induced pluripotent stem cells to a range of target cell types is ubiquitous in monolayer culture. To further improve the phenotype of the cells produced, 3D organoid culture is becoming increasingly prevalent. Mature organoids typically require the involvement of cells from multiple germ layers. The aim of this study was to produce pulmonary organoids from defined endodermal and mesodermal progenitors. Endodermal and mesodermal progenitors were differentiated from iPSCs and then combined in 3D Matrigel hydrogels and differentiated for a further 14 days to produce pulmonary organoids. The organoids expressed a range of pulmonary cell markers such as SPA, SPB, SPC, AQP5 and T1α. Furthermore, the organoids expressed ACE2 capable of binding SARS-CoV-2 spike proteins, demonstrating the physiological relevance of the organoids produced. This study presented a rapid production of pulmonary organoids using a multi-germ-layer approach that could be used for studying respiratory-related human conditions.

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.

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.

Case report: mRNA-1273 COVID-19 vaccine-associated myopericarditis: Successful treatment and re-exposure with colchicine.

Introduction: Vaccine-induced myocarditis is a rare complication of messenger RNA (mRNA) COVID-19 vaccines. Case presentation: We report a case of acute myopericarditis in a recipient of allogeneic hematopoietic cells following the first dose of the mRNA-1273 vaccine and the successful administration of a second and third dose while on prophylactic treatment with colchicine to successfully complete the vaccination. Conclusion: Treatment and prevention of mRNA-vaccine-induced myopericarditis represent a clinical challenge. The use of colchicine is feasible and safe to potentially reduce the risk of this rare but severe complication and allows re-exposure to an mRNA vaccine.

Spotlight on the impact of viral infections on Hematopoietic Stem Cells (HSCs) with a focus on COVID-19 effects.

Hematopoietic stem cells (HSCs) are known for their significant capability to reconstitute and preserve a functional hematopoietic system in long-term periods after transplantation into conditioned hosts. HSCs are thus crucial cellular targets for the continual repair of inherited hematologic, metabolic, and immunologic disorders. In addition, HSCs can undergo various fates, such as apoptosis, quiescence, migration, differentiation, and self-renewal. Viruses continuously pose a remarkable health risk and request an appropriate, balanced reaction from our immune system, which as well as affects the bone marrow (BM). Therefore, disruption of the hematopoietic system due to viral infection is essential. In addition, patients for whom the risk-to-benefit ratio of HSC transplantation (HSCT) is acceptable have seen an increase in the use of HSCT in recent years. Hematopoietic suppression, BM failure, and HSC exhaustion are all linked to chronic viral infections. Virus infections continue to be a leading cause of morbidity and mortality in HSCT recipients, despite recent advancements in the field. Furthermore, whereas COVID-19 manifests initially as an infection of the respiratory tract, it is now understood to be a systemic illness that significantly impacts the hematological system. Patients with advanced COVID-19 often have thrombocytopenia and blood hypercoagulability. In the era of COVID-19, Hematological manifestations of COVID-19 (i.e., thrombocytopenia and lymphopenia), the immune response, and HSCT may all be affected by the SARS-CoV-2 virus in various ways. Therefore, it is important to determine whether exposure to viral infections may affect HSCs used for HSCT, as this, in turn, may affect engraftment efficiency. In this article, we reviewed the features of HSCs, and the effects of viral infections on HSCs and HSCT, such as SARS-CoV-2, HIV, cytomegalovirus, Epstein-Barr virus, HIV, etc. Video Abstract.

Systematic review and meta-analysis of mesenchymal stromal/stem cells as strategical means for the treatment of COVID-19.

BACKGROUND: In coronavirus disease 2019 (COVID-19) patients, elevated levels of inflammatory cytokines from over stimulation of immune cells have become a concern due to the potential outburst of cytokine storm that damages the tissues and organs, especially the lungs. This leads to the manifestation of COVID-19 symptoms, such as pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and eventually death. Mesenchymal stromal/stem cells (MSCs) are currently one of hopeful approaches in treating COVID-19 considering its anti-inflammatory and immunomodulatory functions. On that account, the number of clinical trials concerning the use of MSCs for COVID-19 has been increasing. However, the number of systematic reviews and meta-analysis that specifically discuss its potential as treatment for the disease is still lacking. Therefore, this review will assess the safety and efficacy of MSC administration in COVID-19 patients. OBJECTIVES: To pool evidence on the safety and efficacy of MSCs in treating COVID-19 by observing MSC-related adverse effects as well as evaluating its effects in reducing inflammatory response and improving pulmonary function. DATA SOURCES AND METHODS: Following literature search across six databases and one trial register, full-text retrieval, and screening against eligibility criteria, only eight studies were included for data extraction. All eight studies evaluated the use of umbilical cord-derived mesenchymal stromal/stem cell (UC-MSC), infused intravenously. Of these eight studies, six studies were included in meta-analysis on the incidence of mortality, adverse events (AEs), and serious adverse events (SAEs), and the levels of C-reactive protein (CRP) and interleukin (IL)-6. Meta-analysis on pulmonary function was not performed due to insufficient data. RESULTS: MSC-treated group showed significantly lower risk of mortality than the control group (p = 0.03). No statistical significance was observed on the incidence of AEs (p = 0.78) and SAEs (p = 0.44), and the levels of CRP (p = 0.06) and IL-6 (p = 0.09). CONCLUSION: MSCs were safe for use, with lower risk of mortality and no association with AEs. Regarding efficacy, descriptive analysis showed indications of improvement on the inflammatory reaction, lung clearance, and oxygenation status despite the lack of statistical significance in meta-analysis of CRP and IL-6. Nevertheless, more studies are needed for affirmation. REGISTRATION: This systematic review and meta-analysis was registered on the PROSPERO database (no. CRD42022307730).

New Translational Trends in Personalized Medicine: Autologous Peripheral Blood Stem Cells and Plasma for COVID-19 Patient.

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), still remains a severe threat. At the time of writing this paper, the second infectious wave has caused more than 280,000 deaths all over the world. Italy was one of the first countries involved, with more than 200,000 people reported as infected and 30,000 deaths. There are no specific treatments for COVID-19 and the vaccine still remains somehow inconclusive. The world health community is trying to define and share therapeutic protocols in early and advanced clinical stages. However, numbers remain critical with a serious disease rate of 14%, ending with sepsis, acute respiratory distress syndrome (ARDS), multiple organ failure (MOF) and vascular and thromboembolic findings. The mortality rate was estimated within 2-3%, and more than double that for individuals over 65 years old; almost one patient in three dies in the Intensive Care Unit (ICU). Efforts for effective solutions are underway with multiple lines of investigations, and health authorities have reported success treating infected patients with donated plasma from survivors of the illness, the proposed benefit being protective antibodies formed by the survivors. Plasma transfusion, blood and stem cells, either autologous or allograft transplantation, are not novel therapies, and in this short paper, we propose therapeutic autologous plasma and peripheral blood stem cells as a possible treatment for fulminant COVID-19 infection.