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The Thymic Defect
Published in Miroslav Holub, Immunology of Nude Mice, 2020
On the whole, there are obviously three essential mesenchyme-dependent steps in thymus evolution: (1) humoral induction of the epithelial anlage, (2) direct penetration of mesenchymal cells into the anlage and influx of mesenchymal precursor cells from the bone marrow providing an interdigitating mesh with a high expression of class II MHC antigens and situated mainly in the medulla, and (3) the passage and directed differentiation of lymphoid stem cells. These three steps are strictly coordinalted in time and any deviation may cause some of the numerous thymic dysgenetic events.
An overview of human pluripotent stem cell applications for the understanding and treatment of blindness
Published in John Ravenscroft, The Routledge Handbook of Visual Impairment, 2019
Louise A. Rooney, Duncan E. Crombie, Grace E. Lidgerwood, Maciej Daniszewski, Alice Pébay
The simplest method of hPSC differentiation is commonly referred to as spontaneous differentiation. Using either adherent or suspension culture methodologies, hPSCs differentiate into cell types of each germ layer: ectoderm, endoderm and mesoderm. For many cell lineages, this form of differentiation and growth is inefficient for generation of cells for research. Currently, these protocols are predominantly used for confirming pluripotency of hPSCs, or as a first stage in guided differentiations. Research, usually based on developmental signalling pathways learnt from embryology, has allowed for the development of a multitude of directed differentiation techniques. These can involve co-cultures and/or conditioned media, specific growth factors, small molecules and cell culture medium formulations designed to drive differentiation towards a certain lineage or cell type. More recent methodologies involve the formation of three-dimensional organoids, which show some levels of organisation of the human retina (Ader and Tanaka, 2014). Much work has been undertaken employing these techniques and protocols to differentiate hPSCs to retinal cells.
Islet Transplantation in Type 1 Diabetes: Stem Cell Research and Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
The pancreas is an endocrine organ in vertebrates which is essential for glucose homeostasis via secretion of insulin by beta cells. Autoimmune diseases targeting beta cells result in lack of insulin and, in turn, diabetes mellitus. Developing stem cell replacement therapy for diabetes represents a prime research interest in order to replenish or restore the functions of lost or destroyed islet beta-cells. Considerable research grew for several years, which has discovered the ways to promote differentiation of embryonic stem cells and adult stem or progenitor cells into pancreatic beta-cell lineage. The research has indicated that endocrine and exocrine pancreatic adult progenitor cells can be a potential source of islet beta-cells. The pluripotent ESCs and mesenchymal stem cells can be differentiated with the use of spontaneous or directed differentiation protocol to generate glucose-responding islet cells. The use of ESCs is associated with ethical concerns. Stem cells or mesenchymal stem cells, as well as progenitor cells recovered from readily accessible adult tissues with no or little ethical concerns such as umbilical cord blood stem cells, adipose-derived mesenchymal stem cells, fetal and adult pancreatic duct progenitor cells, are a viable source of islet cells. These tissue-derived adult stem cells can be used in autologous fashion to avoid or minimize the immunological rejection of the transplanted beta cells. The exocrine pancreatic cells, such ductal cells and acinar cells also possess the transdifferentiation capacity to produce insulin-producing cells.
Developing a Reflexive, Anticipatory, and Deliberative Approach to Unanticipated Discoveries: Ethical Lessons from iBlastoids
Published in The American Journal of Bioethics, 2022
Rachel A. Ankeny, Megan J. Munsie, Joan Leach
In less than a week, a fertilized human egg develops from a single cell to a cluster of around 240 cells referred to as a blastocyst. Studying early stages of human development, including the various cell types in the blastocyst, has always been difficult. Animal models provide some insights but key differences in how embryos form and develop limit their relevance (Rossant and Tam 2017). While it is possible to study the cellular and molecular interplay underpinning blastocyst formation and implantation using donated human embryos, their use is limited due to technical, legal, and ethical concerns. Thus researchers have sought to generate models that recapitulate different aspects of early human development in order to shed light into this process. These models rely on human pluripotent stem cells–embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC)–to explore the formation and development of human embryos (known as embryogenesis). While researchers have been able to use pluripotent stem cells to create 3-D structures in vitro that mimic how organs such as the eye, brain, kidney, and liver develop for many years (broadly termed “organoids,” which provides part of the etymology for the neologism “iBlastoid”) (Lancaster and Knoblich 2014), extending directed differentiation of pluripotent stem cells to mimic the earliest stages of human development has only been pursued in recent years.
Differentiation of Human Parthenogenetic Embryonic Stem Cells into Functional Hepatocyte-like Cells
Published in Organogenesis, 2020
Rui Liang, Zhiqiang Wang, Xiangyang Kong, Xiaoxiao Xiao, Tianxing Chen, Hui Yang, Ying Li, Xingqi Zhao
ESCs can be induced to differentiate into target cells by artificial directional induction9,10 via two main routes: via embryoid bodies (EB) or without EB.1112 The EB pathway is a classical method of ES directional differentiation and involves the following basic steps: amplifying ES, removing LIF, forming EB by suspension culture, and inducing their differentiation into target cells. The purpose of the EB pathway is to simulate embryonic development in vivo and provide a microenvironment for ES differentiation. However, the quality of EB obtained is closely related to inoculation density and inoculation size, and directly affects the success of subsequent directional differentiation. The three-dimensional structure of EB accommodates a large number of cells at different differentiation stages. However, it also increases the probability of cell contact inhibition, which prevents optimal absorption of nutrients from the culture medium, leading to aging and death. Moreover, this method is cumbersome and mostly inefficient. Directional differentiation of hESCs can also be achieved without the EB pathway.13 The study of directed ESC differentiation is still in the early stages. Directed differentiation is typically achieved by gradually adding specific cytokines required for the process of embryonic development. For example, to differentiate ESCs into liver cells in vitro, we first add FGF, then HGF, for directed differentiation and development of embryonic liver.
Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?
Published in Expert Opinion on Investigational Drugs, 2020
Michael Ritchie, Ibrahim A. Hanouneh, Mazen Noureddin, Timothy Rolph, Naim Alkhouri
The FGF family of signaling molecules along with FGF receptors (FGFRs) comprise an evolutionarily conserved signaling pathway with far-reaching pleiotropic effects on organogenesis and patterning as well as metabolism [9,10]. Membership in the FGF family does not depend on function but on structural similarities and as such there is a wide variation in binding mechanism, tissue specificity, and physiological response. FGF 1–10 all bind to FGFRs directly while the FGF11 subclass is actually a ‘nuclear FGF’ that does not interact with FGFRs at all [11]. One characteristic of FGFs outside of the FGF19 subfamily is a strong affinity for a heparan sulfate proteoglycan (HSPG) binding domain which allows for sequestration in the extracellular matrix (ECM) [12]. This is theorized to allow rapid growth factor exposure to tissues when there is damage or stress, as in trauma, allowing rapid tissue expansion based on sequestered growth factor directed differentiation and remodeling [12]. FGF19 family proteins show a much weaker affinity for HSPGs, which allows them to evade binding to the ECM. Due to this ability to escape local ECM binding sites, FGF21 is able to circulate and exert systemic, endocrine level effect as opposed to the tissue localized autocrine/paracrine effects exhibited by the other FGF subclasses [11]. Most importantly, multiple animal models have shown significant effects of FGF19 family, specifically FGF21, in regulation of the metabolism of lipids, glucose, and hepatic fibrosis [5,9].