How to establish infrastructures to achieve more efficient regenerative medicine?

The field of regenerative medicine (RM) as an innovative technology has the ability to affect the healthcare system. It develops a variety of techniques through stem cell biology, genetics, bioengineering, biomaterial science, and tissue engineering to replace or restore the role of lost, disabled, or aging cells in the human body. However, the field's proficiency has still been underwhelming at the clinical trial level. This could be due to the innovation of such technologies, as well as their incredible nature. Therefore, managing the infrastructure framework for the safe and efficient application of the aforementioned field of science would help in the process of progress. In this context, the current review focuses on how to establish infrastructures for more effective RM.

Brown adipose tissue and alzheimer's disease.

Alzheimer's disease (AD), the most common type of senile dementia, is a chronic neurodegenerative disease characterized by cognitive dysfunction and behavioral disability. The two histopathological hallmarks in this disease are the extraneuronal accumulation of amyloid-ß (Aß) and the intraneuronal deposition of neurofibrillary tangles (NFTs). Despite this, central and peripheral metabolic dysfunction, such as abnormal brain signaling, insulin resistance, inflammation, and impaired glucose utilization, have been indicated to be correlated with AD. There is solid evidence that the age-associated thermoregulatory deficit induces diverse metabolic changes associated with AD development. Brown adipose tissue (BAT) has been known as a thermoregulatory organ particularly vital during infancy. However, in recent years, BAT has been accepted as an endocrine organ, being involved in various functions that prevent AD, such as regulating energy metabolism, secreting hormones, improving insulin sensitivity, and increasing glucose utilization in adult humans. This review focuses on the mechanisms of BAT activation and the effect of aging on BAT production and signaling. Specifically, the evidence demonstrating the effect of BAT on pathological mechanisms influencing the development of AD, including insulin pathway, thermoregulation, and other hormonal pathways, are reviewed in this article.

Machine Learning: A New Prospect in Multi-Omics Data Analysis of Cancer.

Cancer is defined as a large group of diseases that is associated with abnormal cell growth, uncontrollable cell division, and may tend to impinge on other tissues of the body by different mechanisms through metastasis. What makes cancer so important is that the cancer incidence rate is growing worldwide which can have major health, economic, and even social impacts on both patients and the governments. Thereby, the early cancer prognosis, diagnosis, and treatment can play a crucial role at the front line of combating cancer. The onset and progression of cancer can occur under the influence of complicated mechanisms and some alterations in the level of genome, proteome, transcriptome, metabolome etc. Consequently, the advent of omics science and its broad research branches (such as genomics, proteomics, transcriptomics, metabolomics, and so forth) as revolutionary biological approaches have opened new doors to the comprehensive perception of the cancer landscape. Due to the complexities of the formation and development of cancer, the study of mechanisms underlying cancer has gone beyond just one field of the omics arena. Therefore, making a connection between the resultant data from different branches of omics science and examining them in a multi-omics field can pave the way for facilitating the discovery of novel prognostic, diagnostic, and therapeutic approaches. As the volume and complexity of data from the omics studies in cancer are increasing dramatically, the use of leading-edge technologies such as machine learning can have a promising role in the assessments of cancer research resultant data. Machine learning is categorized as a subset of artificial intelligence which aims to data parsing, classification, and data pattern identification by applying statistical methods and algorithms. This acquired knowledge subsequently allows computers to learn and improve accurate predictions through experiences from data processing. In this context, the application of machine learning, as a novel computational technology offers new opportunities for achieving in-depth knowledge of cancer by analysis of resultant data from multi-omics studies. Therefore, it can be concluded that the use of artificial intelligence technologies such as machine learning can have revolutionary roles in the fight against cancer.

Mesenchymal stem cells' seeded amniotic membrane as a tissue-engineered dressing for wound healing.

Different biomaterials have been used as biological dressing for wound regeneration. For many decades, human amniotic membrane graft (AM) has been widely applied for treating acute and chronic wounds. It has minimal toxicity and immunogenicity, supports mesenchymal cell in-growth, improves epidermal cell adherence and proliferation, and finally is inexpensive and readily available. Enrichment of tissue grafts with the stem cells is a new approach to improve their regenerative effects. This animal study aimed at investigating feasibility, safety, and efficacy of tissue-engineered dressings composed of AM and two different types of mesenchymal stem cells (MSCs) in the excisional wound model in rats. Human adipose-derived MSCs (ADMSCs) and placenta-derived MSCs (PLMSCs) were manufactured from the donated adipose and placenta tissues respectively. After cell characterization, MSCs were seeded on acellular AM (AAM) and cultivated for 5 days. Excisional wound model was developed in 24 male Wistar rats that were randomly classified into four groups including control, AAM, ADMSCs + AAM, and PLMSCs + AAM (n = 6 in each group). Tissue-engineered constructs were applied, and photographs were taken on days 0, 7, and 14 for observing the wound healing rates. In days 7 and 14 post-treatment, three rats from each group were euthanized, and wound biopsies were harvested, and histopathologic studies were conducted. The results of wound closure rate, re-epithelialization, angiogenesis, and collagen remodeling demonstrated that in comparison with the control groups, the MSC-seeded AAMs had superior regenerative effects in excisional wound animal model. Between MSCs group, the PLMSCs showed better healing effect. Our data suggested that seeding of MSCs on AAM can boosts its regenerative effects in wound treatment. We also found that PLMSCs had superior regenerative effects to ADMSc in the rat model of excisional wound.

Looking at time dependent differentiation of mesenchymal stem cells by culture media using MALDI-TOF-MS.

Mesenchymal stem cells (MSCs) are multipotent cells which are popular in human regenerative medicine. These cells can renew themselves and differentiate into several specialized cell types including osteoblasts, adipocytes, and chondrocytes under physiological and experimental conditions. MSCs can secret a lot of components including proteins and metabolites. These components have significant effects on their surrounding cells and also can be used to characterize them. This characterization of multipotent MSCs plays a critical role in their therapeutic potential. The metabolic profile of culture media verified by applying matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF-MS) techniques. Also, the differentiation and development of MSCs have monitored through culture media metabolome or secretome (secreted metabolites). Totally, 24 potential metabolites were identified. Between them 12 metabolites are unique to BM-MSCs and 5 metabolites are unique to AD-MSCs. Trilineage differentiation including chondrocytes, osteoblasts, and adipocytes, as well as metabolites that are being differentiated, have been shown in different weeks. In the present study, the therapeutic effects of MSCs analyzed by decoding the metabolome for MSCs secretome via metabolic profiling using MALDI-TOF-MS techniques.

Metabolomics Signatures of SARS-CoV-2 Infection.

For a very long time, viral infections have been considered as one of the most important causes of death and disability around the world. Through the viral infection, viruses as small pathogens enter the host cells and use hosts' biosynthesis machinery to replicate and collect infectious lineages. Moreover, they can modify hosts' metabolic pathways in order to their own purposes. Nowadays (in 2019-2020), the most famous type of viral infection which was caused by a novel type of coronavirus is called COVID-19 disease. It has claimed the lives of many people around the world and is a very serious threat to health. Since investigations of the effects of viruses on host metabolism using metabolomics tools may have given focuses on novel appropriate treatments, in the current review the authors highlighted the virus-host metabolic interactions and metabolomics perspective in COVID-19.

Regenerative Medicine Perspectives in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common gynecologic endocrine disorder in women between the ages of 15 and 40, with uncertain etiology. It is mostly presented with hyperandrogenism and insulin resistance along with a variety of comorbidities that significantly reduce a patient's quality of life. Many disturbed metabolic pathways are correlated with PCOS. Moreover, it is evident that there is a strong genetic factor for PCOS. Indeed, several altered gene expressions have been found in PCOS subjects, but the exact genetic origins are still unclear. The major treatment options such as pharmacological treatments are to improve the symptoms. In addition, surgical procedures (Bariatric surgery and assisted reproductive technologies) can be used to treat some of the patient's complications and reduce their severity. Generally, using pharmacological agents for a long period of time can increase the risk of adverse effects. Moreover, surgical options may have high-risk consequences. Herein, there is an undeniable need for a different multidisciplinary approach to PCOS. Regenerative medicine with the help of stem cells can develop a worthy alternative approach for the treatment of PCOS. Furthermore, animal models can provide valuable knowledge of genetic alterations and metabolic pathway disturbances in PCOS. They can also be used for testing novel treatments in pre-clinical stages. Therein, the current knowledge of PCOS and investigation about the potential role of regenerative medicine in developing new and more efficient treatments for PCOS are summarized here.

Opportunities and Challenges in Stem Cell Aging.

Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.

Cellular therapy for treatment of spinal cord injury in Zebrafish model.

Spinal cord injury is a serious problem with a high rate of morbidity and mortality for all persons, especially young people (15-25 years old). Due to the large burden and the costs incurred on the government, finding the best therapeutic approach is necessary. In this respect, treatment strategies based on the disease mechanism can be effective. After the first trauma of spinal cord cascades, cellular events happen one after the other known as secondary trauma. The mechanism of secondary events of spinal cord injury could be helpful for target therapy as trying to stop the secondary trauma. Herein, some medical and surgical therapy has been introduced and cell therapy strategy was considered as a recent method. Actually, cell therapy is defined as the application of different cells including mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and some others to replace or reconstruct the damaged tissues and restore their functions. However, as a newly emerged therapeutic method, cell therapy should be used through various subclinical studies in animal models to assess the efficacy of the treatment under controlled conditions. In this review, the role of Zebrafish as a recommended model has been discussed and combinatory approach as the probably most useful treatment has been suggested.

Stem cell-based models and therapies: a key approach into schizophrenia treatment.

Psychiatric disorders such as schizophrenia can generate distress and disability along with heavy costs on individuals and health care systems. Different genetic and environmental factors play a pivotal role in the appearance of the mentioned disorders. Since the conventional treatment options for psychiatric disorders are suboptimal, investigators are trying to find novel strategies. Herein, stem cell therapies have been recommended as novel choices. In this context, the preclinical examination of stem cell-based therapies specifically using appropriate models can facilitate passing strong filters and serious examination to ensure proper quality and safety of them as a novel treatment approach. Animal models cannot be adequately helpful to follow pathophysiological features. Nowadays, stem cell-based models, particularly induced pluripotent stem cells reflected as suitable alternative models in this field. Accordingly, the importance of stem cell-based models, especially to experiment with the regenerative medicine outcomes for schizophrenia as one of the severe typing of psychiatric disorders, is addressed here.

GMP-Compliant Adenoviral Vectors for Gene Therapy.

Recently, gene therapy as one of the most promising treatments can apply genes for incurable diseases treatment. In this context, vectors as gene delivery systems play a pivotal role in gene therapy procedure. Hereupon, viral vectors have been increasingly introduced as a hyper-efficient tools for gene therapy. Adenoviral vectors as one of the most common groups which are used in gene therapy have a high ability for humans. Indeed, they are not integrated into host genome. In other words, they can be adapted for direct transduction of recombinant proteins into targeted cells. Moreover, they have large packaging capacity and high levels of efficiency and expression. In accordance with translational pathways from the basic to the clinic, recombinant adenoviral vectors packaging must be managed under good manufacturing practice (GMP) principles before applying in clinical trials. Therein, in this chapter standard methods for manufacturing of GMP-compliant Adenoviral vectors for gene therapy have been introduced.

GMP-Compliant Human Schwann Cell Manufacturing for Clinical Application.

Schwann cells as glial cells in the peripheral nervous system can participate in neurons protection and forming myelin. Additionally, they are important for nerve pulse conduction supporting along axons. On the other hand, it was demonstrated that they are promising cells for the treatment of demyelinating disorders and also central nervous system damages. Herein, for therapeutic application, Schwann cells should be manufactured based on good manufacturing practice standards to achieve safe and effective clinical products. In this respect, the current chapter tries to introduce a standard protocol for manufacturing of human GMP-compliant Schwann cells for clinical application.

The Outcome of Stem Cell-Based Therapies on the Immune Responses in Rheumatoid Arthritis.

Rheumatoid arthritis as a common autoimmune inflammatory disorder with unknown etiology can affect 0.5-1% of adults in developed countries. It involves more than just the patient's joints and can be accompanied by several comorbidities and affect cardiovascular, pulmonary, and some other systems of the human body. Although cytokine-mediated pathways are mentioned to have a central role in RA pathogenesis, adaptive and innate immune systems and intracellular signaling pathways all have important roles in this process. Non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying anti-rheumatic drugs, and biological agents are some mentioned medications used for RA. They are accompanied by some adverse effects and treatment failures which elucidates the needing for novel and more powerful therapeutic approaches. Stem cell-based therapies and their beneficial effects on therapeutic processes of different diseases have been founded so far. They can be an alternative and promising therapeutic approach for RA, too; due to their effects on immune responses of the disease. This review, besides some explanations about RA characteristics, addresses the outcome of the stem cell-based therapies including mesenchymal stem cell transplantation and hematopoietic stem cell transplantation for RA and explains their effects on the disease improvement.

The Design and Application of an Appropriate Parkinson's Disease Animal Model in Regenerative Medicine.

OBJECTIVES: Aging as an inevitable and complex physiological process occurs through a progressive decrease in the potential of tissue regeneration. Given the increasing global outbreak of aging and age-related disorders, it is important to control this phenomenon. Parkinson's disease (one of the age-related neurodegenerative and progressive disorders) resulted from predominant dopaminergic neurons deficiency. Usual Parkinson's disease treatments just can lead to symptomatically relieving. Recently, cell therapy and regenerative medicine a great promise in the treatment of several types of disorders including Parkinson's disease. Herein, before starting clinical trials, preclinical studies should be performed to answer some fundamental questions about the safety and efficacy of various treatments. Additionally, developing a well-designed and approved study is required to provide an appropriate animal model with strongly reliable validation methods. Hereupon, this review will discuss about the design and application of an appropriate Parkinson's disease animal model in regenerative medicine. EVIDENCE ACQUISITION: In order to conduct the present review, numbers of Parkinson's disease preclinical studies, as well as literatures related to the animal modeling, were considered. RESULTS: Appropriate animal models which approved by related authorize committees should have a high similarity to humans from anatomical, physiological, behavioral, and genetic characteristics view of point. CONCLUSION: It is concluded that animal studies before starting clinical trials have an important role in answering the crucial questions about the various treatments safety and efficacy. Therein, it is recommended that all of animal modeling stages be assessed by animal ethics and welfare guidelines and also evaluated by different validation tests. However, it is better to find some alternatives to replacement, refinement, and, reduction of animals. Nowadays, some novel technologies such as using imaging methods have been introduced.

Cell Therapy Targets for Autism Spectrum Disorders: Hopes, Challenges and Future Directions.

Autism spectrum disorders as a group of pediatric neurodevelopmental diseases is a crucial part of the worldwide disabilities which have influence in communication skills, social interactions, and ability to understand the concepts. The precise pathophysiology of autism spectrum disorders due to the abundance of involved mechanisms is unknown. Some of these involved mechanisms are related to genetic factors, chronic neuro inflammation, mitochondrial dysfunction, oxidative stress, immune dysregulation, hormonal imbalance, and environmental factors. Current main treatments for autisms are behavioral, nutritional and medical therapies, however there is not definitive treatment approach. Therein, more novel therapies are still required to improve the symptoms. Several preclinical and clinical evidence were shown that stem cell therapy is a potential treatment option for autism spectrum disorders individuals. Considering the significant factors which can affect the outcome of stem cell therapeutic effects including stem cell types, route and dosage of administration, and mechanism of activity along with selecting best animal models can be very important in performing clinical trials.

Gene Therapy as an Emerging Therapeutic Approach to Breast Cancer: New Developments and Challenges.

Breast cancer is a heterogeneous disease, which is the consequence of several genetic and environmental factors. Also, it is one of the most common causes of cancer death and second leading cancer among women all around the world. Therefore, it is necessary to develop novel therapeutic approaches useful for the successful treatment of breast cancer. As conventional treatments had limited success, alternative approaches for the treatment of breast cancer have been applied in recent years. Hence, the molecular basis of breast cancer has provided the opportunity of using genetic materials for therapeutic uses. In this regard, gene therapy as one of the potentially efficient and beneficial treatments among various techniques became a popular treatment for different cancers, especially breast cancer. Accordingly, there are plenty of targets available for gene therapy of breast cancer. Gene therapy strategies have the potential to correct molecular defects that contributed to the cancer progression. These techniques should selectively target tumor cells without affecting normal cells. Moreover, data of clinical trials in gene therapy for breast cancer indicated that this approach has little toxicity compared to other therapeutic approaches. In this study, different aspects of breast neoplasm, gene therapy techniques, challenges, and recent developments will be mentioned.

Mesenchymal stem cell as a novel approach to systemic sclerosis; current status and future perspectives.

Systemic sclerosis is a rare chronic autoimmune disease with extensive microvascular injury, damage of endothelial cells, activation of immune responses, and progression of tissue fibrosis in the skin and various internal organs. According to epidemiological data, women's populations are more susceptible to systemic sclerosis than men. Until now, various therapeutic options are employed to manage the symptoms of the disease. Since stem cell-based treatments have developed as a novel approach to rescue from several autoimmune diseases, it seems that stem cells, especially mesenchymal stem cells as a powerful regenerative tool can also be advantageous for systemic sclerosis treatment via their remarkable properties including immunomodulatory and anti-fibrotic effects. Accordingly, we discuss the contemporary status and future perspectives of mesenchymal stem cell transplantation for systemic sclerosis.

Zebrafish for Personalized Regenerative Medicine; A More Predictive Humanized Model of Endocrine Disease.

Regenerative medicine is a multidisciplinary field that aims to determine different factors and develop various methods to regenerate impaired tissues, organs, and cells in the disease and impairment conditions. When treatment procedures are specified according to the individual's information, the leading role of personalized regenerative medicine will be revealed in developing more effective therapies. In this concept, endocrine disorders can be considered as potential candidates for regenerative medicine application. Diabetes mellitus as a worldwide prevalent endocrine disease causes different damages such as blood vessel damages, pancreatic damages, and impaired wound healing. Therefore, a global effort has been devoted to diabetes mellitus investigations. Hereupon, the preclinical study is a fundamental step. Up to now, several species of animals have been modeled to identify the mechanism of multiple diseases. However, more recent researches have been demonstrated that animal models with the ability of tissue regeneration are more suitable choices for regenerative medicine studies in endocrine disorders, typically diabetes mellitus. Accordingly, zebrafish has been introduced as a model that possesses the capacity to regenerate different organs and tissues. Especially, fine regeneration in zebrafish has been broadly investigated in the regenerative medicine field. In addition, zebrafish is a suitable model for studying a variety of different situations. For instance, it has been used for developmental studies because of the special characteristics of its larva. In this review, we discuss the features of zebrafish that make it a desirable animal model, the advantages of zebrafish and recent research that shows zebrafish is a promising animal model for personalized regenerative diseases. Ultimately, we conclude that as a newly introduced model, zebrafish can have a leading role in regeneration studies of endocrine diseases and provide a good perception of underlying mechanisms.

Prospect of Stem Cell Therapy and Regenerative Medicine in Osteoporosis.

The field of cell therapy and regenerative medicine can hold the promise of restoring normal tissues structure and function. Additionally, the main targets of stem cell-based therapies are chronic diseases and lifelong disabilities without definite cures such as osteoporosis. Osteoporosis as one of the important causes of morbidity in older men and post-menopausal women is characterized by reduced bone quantity or skeletal tissue atrophy that leads to an increased risk of osteoporotic fractures. The common therapeutic methods for osteoporosis only can prevent the loss of bone mass and recover the bone partially. Nevertheless, stem cell-based therapy is considered as a new approach to regenerate the bone tissue. Herein, mesenchymal stem cells as pivotal candidates for regenerative medicine purposes especially bone regeneration are the most common type of cells with anti-inflammatory, immune-privileged potential, and less ethical concerns than other types of stem cells which are investigated in osteoporosis. Based on several findings, the mesenchymal stem cells effectiveness near to a great extent depends on their secretory function. Indeed, they can be involved in the establishment of normal bone remodeling via initiation of specific molecular signaling pathways. Accordingly, the aim herein was to review the effects of stem cell-based therapies in osteoporosis.

OMICS insights into cancer histology; Metabolomics and proteomics approach.

Metabolomics as a post-genomic research area comprising different analytical methods for small molecules analysis. One of the underlying applications of metabolomics technology for better disease diagnosis and prognosis is discovering the metabolic pathway differences between healthy individuals and patients. On the other hand, the other noteworthy applications of metabolomics include its effective role in biomarker screening for cancer detection, monitoring, and prediction. In other words, emerging of the metabolomics field can be hopeful to provide a suitable alternative for the common current cancer diagnostic methods especially histopathological tests. Indeed, cancer as a major global issue places a substantial burden on the health care system. Hence, proper management can be beneficial. In this respect, formalin-fixed paraffin-embedded tissue specimens (in histopathological tests) are considered as a valuable source for metabolomics investigations. Interestingly, formalin-fixed paraffin-embedded tissue specimens can provide informative data for cancer management. In general, using these specimens, determining the cancer stage, individual response to the different therapies, personalized risk prediction are possible and high-quality clinical services are the promise of OMICS technologies for cancer disease. However, considering all of these beneficial characteristics, there are still some limitations in this area that need to be addressed in order to optimize the metabolomics utilizations and advancement.