Cellular differentiation is a biological process in which a cell permanently alters its characteristics (phenotype), ensuring that its descendants also inherit these traits or can modify them when subjected to other differentiating stimuli. During this process, genetic changes occur within cells, leading to a commitment to a specific cell fate. Totipotent cells (stem cells) undergo differentiation based on their ultimate cell destiny, dictated by the tissue they will eventually become a part of it. A current challenge in regenerative medicine involves employing biomaterials within hydrogel matrices to induce changes in cell phenotype and functionality. Stem cells from various sources can thrive within 3D biomatrices featuring defined chemical compositions, and depending on the physical, chemical, and biological cues encountered, they can assume diverse phenotypes. The utilization of hydrogels composed of natural and synthetic polymers, as well as inorganic components, has been explored for such purposes, revealing a direct correlation between the structure and physicochemical properties of polymeric matrices and their impact on cell differentiation capacity. Consequently, the encapsulation of stem cells within these biomaterials can be tailored to enhance the effectiveness of regenerative medicine treatments, particularly in the regeneration of cardiac, dermal, epithelial, cartilaginous, and nervous tissues. This chapter aims to elucidate the fundamental principles of cellular differentiation in stem cells facilitated by biomaterial compositions within hydrogel matrices and explore its potential applications in regenerative medicine.
Embryology is a part of anatomical sciences investigating formation, differentiation, growth and development of embryos and fetuses. This science is not only limited to the definition above, but it can also be used for human adults involved in perinatology, infertility, congenital defects, cell therapy and personalized medicine. This chapter aims to introduce embryology and its role in the clinical practice of physicians. The linkage of embryology and medicine is an example of the linkage between basic and clinical medical sciences. Entering to this interdisciplinary field opens a novel door for making hypotheses for future studies.
Every human is a result of a cell formed from the fertilization of an oocyte with a sperm. This cell is called a zygote. A miracle is how just one cell can make a lot of tissues and organs. Regulation of gene expression is the first step of tissue development. Regulation of gene expression has different levels, including the genome (DNA content), transcriptome (RNA content, resulted from the transcription of DNA), and proteome (protein content, resulted from the translation of RNA) levels. The final consequence of gene expression regulation is cellular phenotype. The resulted proteins act for inter-cellular signaling transduction and tissue development. We aimed to show the details of gene expression regulation, cellular signaling transduction and interaction, and tissue development. We have shown a scheme of the gene to fetus formation.
Stem cells hold a great promise for regenerative medicine given their ability to proliferate and differentiate into various cell types. However, self-renewal and multipotency also grant a high capacity to form tumor tissues in vivo post-therapeutic administration. Indeed, multiple case reports have revealed the formation of stem cell derived tumors, such as teratoma, in animal models and even in clinical applications. As a result, examination of tumorigenicity becomes one of the major considerations when assessing the safety of stem cell-derived therapeutic products. Ideally, the assessment needs to be performed in a rapid, sensitive, cost-effective, and scalable manner. In this chapter, the current practices of assay development to fulfill this demand are reviewed. Progress in animal models, soft agar culture, PCR, flow cytometry, and microfluidics are introduced and compared comprehensively. Some insights regarding the assay selection and future development are also provided as there is no one-for-all assay at this moment.
Sepsis is a life-threatening syndrome that develops as a result of a dysregulated immune response caused by an infectious agent. The pathogenesis of sepsis has been better understood over the years, and new treatment protocols have been developed. In sepsis, the host immune response is equally as important as the infectious agent in the clinical presentation of sepsis and the development of shock. In the early phase of sepsis, hyperinflammation and secondary hyperinflammation occur, while in the late phase, immunosuppression is present. Sepsis treatment is based on controlling the source of infection, antimicrobial treatment and supportive treatment depending on the phase of sepsis. Stem cells have shown great potential in recent years to become a new therapeutic option for infectious diseases. The stem cell is an undifferentiated cell that can selfrenew to proliferate and differentiate into specialized cells under appropriate conditions. The following section focuses on stem cell therapy, which is an adjuvant treatment method in the treatment of sepsis. Mesenchymal stem cells (MSCs) have immunomodulatory properties through direct or paracrine interactions with immune cells involved in innate or adaptive immunity. In the treatment of sepsis, MSCs have shown promise in reducing mortality and bacteremia in experimental mouse models of sepsis. However, the number of completed clinical trials on sepsis is very limited. These studies have shown the use of MSCs to be safe at appropriate doses. Nevertheless, there may be a risk of thromboembolic events following high-dose applications. There remains a need for clinical studies on timing, dose and duration of use.
After the development of a new drug, it is compulsory to test its benefits as well as toxic effects before human implementation. In the past, animals were being used as standard models for drug toxicity testing, but animal testing arose many ethical concerns and controversies. To overcome these ethical hurdles, many non-animal toxicity models were developed to cope with the drug toxicity analysis, but certain limitations like interspecies barriers do not make them good models for drug toxicity studies.-. Due to their self-renewal and capacity to divide into multiple cell lineages, such as hepatocytes, cardiomyocytes, and neural cells, stem cells are being used to establish alternative approaches for toxicological studies. This makes them a potential resource in predictive toxicological studies without the limitations of interspecies boundaries. In-vitro toxicological models, such as Adult Stem Cells (ASCs), Embryonic Stem Cells (ESCs), and recently established Induced Pluripotent Stem Cells (iPSCs) are currently being used as alternatives to animal models. This chapter will discuss the journey of toxicity studies from animal models to in vitro stem cell-based toxicity models.
Every species in this world, from the simplest to complex organisms, hasauto-capacity for tissue regeneration. Tissue regeneration is a process of renewal andgrowth that replaces or repairs damaged or lost tissue as a result of natural changes ordisturbances. As organisms become more complex, their regenerative abilitydiminishes. As humans are complex having very limited regenerative capability, tissueregeneration has become one of growing areas of research. However, it has become aresource-intensive research as it is dependent on the availability and ability of the cellsused. The need to find an available source of cells led researchers to choose stem cells.The use of stem cells has shown excellent progress in tissue regeneration and numeroustypes of stem cells have been reported to be used in tissue regeneration, namelymesenchymal stem cells, neural stem cells, adipose stem cells, cardiac stem cells,induced pluripotent stem cells etc. However, the potential use of dental stem cells inregenerative medicine has not been widely discussed. Dental stem cells, which werefirst discovered in 1985 have been very well-characterized for their potential to be usedin dental tissue regeneration, but less recognized for application in other parts of thebody. Therefore, this chapter focusses on the potential use of dental stem cells,particularly stem cells from human exfoliated deciduous teeth (SHED) for tissueregeneration. SHED are adult stem cells that can be retrieved from primary teeth. Sincethese cells can be acquired after extraction of deciduous teeth, they provide noninvasive,unlimited cell sources without any ethical concerns. They are multipotentstem cells with a higher proliferation rate and differentiation capability than otherdental stem cells and human bone marrow mesenchymal stem cells. Therefore, thischapter will specifically address the differentiation potential of SHED, particularly withrespect to fibroblasts, epithelial and osteoblast-like cells, growth factors and thesignalling pathways involved. Knowledge about the differentiation potential of SHEDis important because it creates a plethora of opportunities as an excellent stem cellmodel for tissue regeneration. Keeping this in mind, this chapter aims to provideinformation to the researchers, students, and scientists working or interested inexploring the SHED on tissue regeneration.
The aging of the population goes along with age-related diseases, such as osteoporosis, a disorder of bone remodeling. Bone homeostasis is maintained by bonebuilding osteoblasts and bone-resorbing osteoclasts. During osteoporosis, this balance is disturbed by augmented bone resorption, which leads to an increased risk of bone fractures, with potentially lethal consequences. To battle this, various drugs with different target sites are used. Currently, the gold standard osteoporosis medications are the bisphosphonates, which induce apoptosis of the osteoclasts. However, bisphosphonates may cause adverse effects, such as osteonecrosis of the jawbone. Other available drugs for bone metabolism disorders also exhibit undesired side- and off-target effects of varying severity. Thus, new potential drug candidates are being developed, some already reached phase II or phase III clinical trials. The modes of action of these drug candidates range from anti-resorptive to osteoanabolic therapies. Osteoanabolic therapies stimulate the formation of bone, while anti-resorptive therapies decrease the bone resorption. Most anti-resorptive therapies induce apoptosis of the osteoclasts, which negatively affects the osteoblasts as well since there is a feedback loop between these two cell types. A better understanding of bone homeostasis, beginning with the differentiation pathways of mesenchymal stem cells towards osteoblasts and hematopoietic stem cells towards osteoclasts and their interactions during these differentiation processes are of increasing interest for future osteoporosis treatments with minimal side effects. This chapter focuses on the differentiation and signaling pathways of osteoblasts and osteoclasts. In addition, new osteoporosis drugs are illuminated from the biological and the chemical point of view. Their progress from bench to bedside is presented.
In embryonic development and throughout life, there are some cells can exhibit phenotypic plasticity. Phenotypic plasticity is the ability of cells to differentiate into multiple lineages. In normal development, plasticity is highly regulated whereas cancer cells re-activate this dynamic ability for their own progression. The re-activation of these mechanisms enables cancer cells to acquire a cancer stem cell (CSC) phenotype- a subpopulation of cells with increased ability to survive in a hostile environment and resist therapeutic insults. There are several contributors fuel CSC plasticity in different stages of disease progression such as a complex network of tumour stroma, epidermal microenvironment and different sub-compartments within tumour. These factors play a key role in the transformation of tumour cells from a stable condition to a progressive state. In addition, flexibility in the metabolic state of CSCs helps in disease progression. Moreover, epigenetic changes such as chromatin, DNA methylation could stimulate the phenotypic change of CSCs. Development of resistance to therapy due to highly plastic behaviour of CSCs is a major cause of treatment failure in cancers. However, recent studies explored that plasticity can also expose the weaknesses in CSCs, thereby could be utilized for future therapeutic development. Therefore, in this review, we discuss how cancer cells acquire the plasticity, especially the role of the normal developmental process, tumour microenvironment, and epigenetic changes in the development of plasticity. We further highlight the therapeutic resistance property of CSCs attributed by plasticity. Also, outline some potential therapeutic options against plasticity of CSCs. Graphical Abstract .
Mesenchymal stem cells (MSCs) have been widely used in the areas of tissue engineering and regenerative medicine due to their wide differentiation potential into various lineages. The stem cell/material interface involved is a complex microenvironment where material can direct the stem cell’s fate through its inherent properties (such as stiffness, surface topography and/or surface chemistry, and nanoparticles themselves, etc.). Stem cells in contact with materials are able to sense their properties and translate parallel signaling information into stem cell lineage commitment and differentiation. These materials can be utilized as scaffolds for tissue engineering and regenerative medicine and as nanoparticles for drug delivery or cell tracking. Thus, it is of vital importance to investigate the effects of material properties on the differentiation of MSCs to give a better design of biomaterials. With this in mind, we summarize the recent reports about the effects of materials properties (such as stiffness, surface topography and/or surface chemistry, and nanoparticles themselves, etc.) on the differentiation of MSCs. We also overview a subset of the possible mechanisms proposed to explain how the material properties affect the differentiation of MSCs.
