Research progress on Mesenchymal Stem Cells (MSCs), Adipose-Derived Mesenchymal Stem Cells (AD-MSCs), Drugs, and Vaccines in Inhibiting COVID-19 Disease

Mesenchymal Stem Cells (MSCs), and Adipose-Derived Mesenchymal Stem Cells (AD-MSCs) have been used for many years in regenerative medicine for clinical and surgical applications. Additionally, recent studies reported improved respiratory activity after intravenous administration of MSCs into patients affected by coronavirus disease 2019 (COVID-19) caused by the Coronavirus 2 (SARS-CoV-2) suggesting their role as anti-viral therapy. Severe COVID-19 patients usually progress to acute respiratory distress syndrome, sepsis, metabolic acidosis that is difficult to correct, coagulation dysfunction, multiple organ failure, and even death in a short period after onset. Currently, there is still a lack of clinically effective drugs for such patients. The high secretory activity, the immune-modulatory effect, and the homing ability make MSCs and in particular AD-MSCs both a potential tool for the anti-viral drug-delivery in the virus microenvironment and potential cellular therapy. AD-MSCs as the most important exponent of MSCs are expected to reduce the risk of complications and death of patients due to their strong anti-inflammatory and immune-modulatory capabilities, which can improve microenvironment, promote neovascularization and enhance tissue repair capabilities. In this literature review, the role of regenerative strategies through MSCs, AD-MSCs, and adipocyte-secreted exosomal microRNAs (A-SE-miRs) as a potential antiviral therapy was reported, comparing the results found with current research progress on drugs and vaccines in COVID-19 disease

Isolated Cardiac Metastasis from Colorectal Cancer in a 35-Year-Old Man

We present the case of a 35-year-old patient who was found to be affected by an isolated clinically silent cardiac metastasis despite a negative CT follow-up at one year from abdominal surgery for colorectal cancer. CT/PET and tumor marker GICA were fundamental in suggesting the diagnosis, which was then confirmed by cardiac magnetic resonance and surgical biopsy. This is a very rare modality of presentation of cardiac metastasis because of the young age of our patient and the absence of disease in other sites

Bone regeneration process driven to human periodontal ligament stem cells cultured onto corticocancellous scaffold

The aim of our research was to develop tissue-engineerized constructs composed by porcine cortico-cancellous scaffold (Osteobiol Dual Block) (DB) and xenofree ex vivo culture of human Periodontal Ligament Stem Cells (hPDLSCs) induced to osteogenic differentiation. hPDLSCs placed in xeno-free media formulation mantained the stem cells features, the expression of stemness and pluripotency markers, and the capacity to differentiate in different mesenchymal cell lines (1). Micrographs performed by transmission electron microscopy suggested that after one week of culture, both uninduced and osteogenic induced cells joined and grew on DB secreting extracellular matrix, hierarchically assembled in fibrils in osteogenic differentiation induced samples (2). Quantitative RT-PCR (qRT-PCR) of 92 osteogenesis-related assays of hPDLSCs seeded on the DB showed the upregulation of key genes involved in the osteogenic differentiation pathway such as RUNX2, collagens and SMAD. hPDLSCs induced to osteogenic differentiation in presence of DB expressed osteogenic- related transcripts such as BMP1-4-6, RUNX-2, collagens, MSX1-2, TGFβ3 and SMAD. Functional study revealed a significant increased response of calcium transients, in presence of the 3D-DB both in undifferentiated and differentiated cells stimulated with calcitonin and parathormone, suggesting that the biomaterial could drive the osteogenic differentiation process of hPDLSCs. These data were confirmed from the increase of gene expression of L-type voltage-dependent Ca2+ (VDCCL), subunits α1C and α2D1 in undifferentiated cells in presence of DB. Our results propose to consider DB a biocompatible, osteoinductive and osteoconductive biomaterial making it promising tools to regulate cell activities in biological environments and for a potential use for the development of new custom made tissue-engineering

A randomized blinded retrospective study: the combined use of micro-needling technique, low-level laser therapy and autologous non-activated platelet-rich plasma improves hair re-growth in patients with androgenic alopecia

Introduction Mini-invasive therapies based on autologous non-activated Platelet-Rich Plasma (ANA-PRP), Low-Level Laser Therapy (LLL-T), and Micro-Needling Technique (MN-T) used in combining for hair re-growth need to be standardized. Objectives The work aims to showin vivooutcomes resulted from retrospective case-series study in which ANA-PRP + MN-T + LLL-T were used in combined in patients affected by Androgenic alopecia. Methods 23 patients were treated, of which 13 males were classified in stage I-V by the Norwood-Hamilton scale, and 10 females were classified in stage I-III by the Ludwig scale. Assessment of hair re-growth was evaluated with photography, physician's and patient's global assessment scale, and standardized phototrichograms during a follow-up: T0 - baseline, T1 - 12 weeks, T2 - 23 weeks, T3 - 44 weeks, T4 - 58 weeks. Results Interesting outcomes represented by a hair density increase of 81 +/- 5 hairs/cm(2)and 57 +/- 7 hairs/cm(2)respectively at T1 and T2 compared with baseline (173 +/- 5 hairs/cm(2)at T1 and 149 +/- 9 hairs/cm(2)at T2 versus 92 +/- 2 hairs/cm(2)at baseline) were observed using computerized trichograms. Expert Opinion The main limitation in the autologous regenerative therapies and biotechnologies in hair-regrowth is the extreme variability of PRP products used, in the absence of standardized protocols and widely shared. Appropriate PRP preparations have to be pick after carefully thinking about their bio-molecular specifications and intended indications for use in patients. This approach will aid in matching the optimal PRP product to specific patient factors, leading to improved outcomes and the elucidation of the cost-effectiveness of this treatment. The combined use of biotechnologies as the association of PRP with micro-needling and low-level laser therapy may improve the results in terms of hair count and hair density compared with those obtained by alone PRP. All the procedures must be performed in the full respect of international and local rules. Conclusions The effect of the combined use of MN-T, LLL-T, and ANA-PRP has been demonstrated

Systematic Review: Allogenic Use of Stromal Vascular Fraction (SVF) and Decellularized Extracellular Matrices (ECM) as Advanced Therapy Medicinal Products (ATMP) in Tissue Regeneration

Stromal vascular fraction (SVF) containing adipose stem cells (ASCs) has been used for many years in regenerative plastic surgery for autologous applications, without any focus on their potential allogenic role. Allogenic SVF transplants could be based on the possibility to use decellularized extracellular matrix (ECM) as a scaffold from a donor then re-cellularized by ASCs of the recipient, in order to develop the advanced therapy medicinal products (ATMP) in fully personalized clinical approaches. A systematic review of this field has been realized in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) guidelines. Multistep research of the PubMed, Embase, MEDLINE, Pre-MEDLINE, PsycINFO, CINAHL, Clinicaltrials.gov, Scopus database, and Cochrane databases has been conducted to identify articles and investigations on human allogenic ASCs transplant for clinical use. Of the 341 articles identified, 313 were initially assessed for eligibility on the basis of the abstract. Of these, only 29 met all the predetermined criteria for inclusion according to the PICOS (patients, intervention, comparator, outcomes, and study design) approach, and 19 have been included in quantitative synthesis (meta-analysis). Ninety-one percent of the studies previously screened (284 papers) were focused on the in vitro results and pre-clinical experiments. The allogenic use regarded the treatment of perianal fistulas, diabetic foot ulcers, knee osteoarthritis, acute respiratory distress syndrome, refractory rheumatoid arthritis, pediatrics disease, fecal incontinence, ischemic heart disease, autoimmune encephalomyelitis, lateral epicondylitis, and soft tissue defects. The information analyzed suggested the safety and efficacy of allogenic ASCs and ECM transplants without major side effects

Morphological and cytofluorimetric analysis of adult mesenchymal stem cells expanded ex vivo from periodontal ligament.

Many adult tissues contain a population of stem cells that have the ability of regeneration after trauma, disease or aging. Recently, there has been great interest in mesenchymal stem cells and their roles in maintaining physiological structure tissues and their studies have been considered very important and intriguing after having shown that this cell population can be expanded ex vivo to regenerate tissues not only of the mesenchymal lineage, such as intervertebral disc cartilage, bone, tooth-associated tissue, cardiomyocytes, but also to differentiate into cells derived from other embryonic layers, including neurons. Currently, different efforts have been focused on the identification of odontogenic progenitors from oral tissues. In this study we isolated and characterized a population of homogeneous human mesenchymal stem cells proliferating in culture with an attached well-spread morphology derived from periodontal ligament, tissue of ectomesenchymal origin, with the ability to form a specialized joint between alveolar bone and tooth. The adherent cells were harvested and expanded ex vivo under specific conditions and analysed by FACScan flow cytometer and morphological analysis was carried out by light, scanning and transmission electron microscopy. Our results displayed highly evident cells with a fibroblast like morphology and a secretory apparatus, probably indicating, that the enhanced function of the secretory apparatus of the mesenchymal stem cells may be associated with the secretion of molecules that are required to survive and proliferate. Moreover, the presence in periodontal ligament of CD90, CD29, CD44, CD166, CD 105, CD13 positive cells, antigens that are also identified as stromal precursors of the bone marrow, indicate that the periodontal ligament may turn out to be a new efficient source of the cells with intrinsic capacity to self-renewal, high ability to proliferate and differentiate, that can be utilized for a new approach to regenerative medicine and tissue engineering

Development of Xeno-free culture system for human Periodontal Ligament Stem Cells

The opportunity of transplanting adult stem cells into damaged organs has opened new prospectives for the treatment of several human pathologies. Aim of this study was to develop a culture system for the expansion and production of human Periodontal Ligament Stem Cells (hPDLSCs) using a new xeno-free media formulation ensuring the maintenance of the stem cells features comprising: the multiple passage expansion, mesengenic lineage differentiation, cellular phenotype and genomic stability, essential elements for conforming to translation to cell therapy1. Somatic stem cells were isolated from the human periodontium using a minimally invasive periodontal access flap surgery. Expanded hPDLSCs in a xeno-free culture showed the morphological features of stem cells, expressed the markers associated with pluripotency, and a normal karyotype. Under appropriate culture conditions, hPDLSCs presented adipogenic and osteogenic potential; indeed, a very high accumulation of lipid droplets was evident in the cytoplasm of adipogenic induced cells, and indisputable evidence of osteogenic differentiation, investigated by transmission electron microscopy, and analyzed for gene expression analysis has been shown2. Our results prove that the novel xeno-free culture method might provide the basis for GMP culture of autologous stem cells, readily accessible from human periodontium, and can be a resource to facilitate their use in human clinical studies for potential therapeutic regeneration

5-Aza Exposure Improves Reprogramming Process Through Embryoid Body Formation in Human Gingival Stem Cells

Embryoid bodies (EBs) are three-dimensional aggregates formed by pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells. They are used as an in vitro model to evaluate early extraembryonic tissue formation and differentiation process. In the adult organisms, cell differentiation is controlled and realized through the epigenetic regulation of gene expression, which consists of various mechanisms including DNA methylation. One demethylating agent is represented by 5-Azacytidine (5-Aza), considered able to induce epigenetic changes through gene derepression. Human gingival mesenchymal stem cells (hGMSCs), an easily accessible stem cells population, migrated from neural crest. They are particularly apt as an in vitro study model in regenerative medicine and in systemic diseases. The ability of 5-Aza treatment to induce hGMSCs toward a dedifferentiation stage and in particular versus EBs formation was investigated. For this purpose hGMSCs were treated for 48 h with 5-Aza (5 μM). After treatment, hGMSCs are organized as round 3D structures (EBs-hGMSCs). At light and transmission electron microscopy, the cells at the periphery of EBs-hGMSCs appear elongated, while ribbon-shaped cells and smaller cells with irregular shape surrounded by extracellular matrix were present in the center. By RT-PCR, EBs-hGMSCs expressed specific transcription markers related to the three germ layers as MAP-2, PAX-6 (ectoderm), MSX-1, Flk-1 (mesoderm), GATA-4, and GATA-6 (endoderm). Moreover, in EB-hGMSCs the overexpression of DNMT1 and ACH3 other than the down regulation of p21 was detectable. Immunofluorescence staining also showed a positivity for specific etodermal and mesodermal markers. In conclusion, 5-Aza was able to induce the direct conversion of adult hGMSCs into cells of three embryonic lineages: endoderm, ectoderm, and mesoderm, suggesting their possible application in autologous cell therapy for clinical organ repair

Current Evidence on Bisphenol A Exposure and the Molecular Mechanism Involved in Related Pathological Conditions

Bisphenol A (BPA) is one of the so-called endocrine disrupting chemicals (EDCs) and is thought to be involved in the pathogenesis of different morbid conditions: immune-mediated disorders, type-2 diabetes mellitus, cardiovascular diseases, and cancer. The purpose of this review is to analyze the mechanism of action of bisphenol A, with a special focus on mesenchymal stromal/stem cells (MSCs) and adipogenesis. Its uses will be assessed in various fields: dental, orthopedic, and industrial. The different pathological or physiological conditions altered by BPA and the related molecular pathways will be taken into consideration