Current Topics in Medicinal Chemistry - Volume 11, Issue 13, 2011

In last ten years, research field in stem cells has garnered a lot of attention from researchers and clinicians due to several reasons. Studies on human embryonic stem (hES) cells have potential to unfold the information about the complex events that occur during human development. The most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Stem cells differentiated into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat a number of diseases including Alzheimer's diseases, spinal cord injury, stroke, burns, heart diseases, diabetes, osteoarthritis, and rheumatoid arthritis to name a few. Furthermore, some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. Studies of stem cells offer a more complete understanding of the genetic and molecular controls of these processes that may yield information about how such diseases arise and may reveal new strategies for therapies. Human stem cells could also be used to test new drugs. Other kinds of cell lines are already being used in this way. The availability of pluripotent stem cells allow drug testing in a wider range of cell types. The present issue of “Stem Cells” covers the potential use of stem cells in various pathological conditions in clinical setup. Dhawan et al. have descried the current understanding of stem cell organization and that of Cancer Stem Cells (CSC) within the colonic epithelium and have discussed the potential role of CSCs in the development and/or progression of CSC and have proposed them as targets for therapeutic interventions. Didwania et al. have discussed about the production of red blood cells from human embryonic stem cell and have proposed the production of red blood cell using bioreactor. Authors also have presented a mathematical model to describe the dynamics of expansion, and maintenance of homeostasis in the bioreactor. They have described cell expansion in the artificial hematopoietic stem cell niche in order to design and optimize a scaled-up red blood cell production in bioreactor. Whereas Dr. Pillai has discussed the potential strategies for using stem cells in clinical set up including stem cell sources, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct ocular-lineage differentiation of stem cells for complete or partial eye regeneration and research. This article discusses the broad introduction to the stem cell-mediated correction of eye ailments and provides extensive references for interested readers. This paper also looks into the different aspects of using stem cells for drug development for treating eye ailments. The main challenge of the stem cell transplant is the immunorejection of stem cell by the host tissue. The article written by Thompson et al summarizes various ways to overcome this potential problem. They discuss the challenges faced to in vitro development of a bona fide ESC-derived hematopoietic stem cells and their differentiation fate in vivo, and provide suggestions to predict the immunogenicity of specific ESC-derived hematopoietic populations before transplantation that could be used to prevent their rejection after transplantation into an adult host. The article by Talbot summarizes the possible use of stem cell biology to study the toxic effect of chemicals on the cells. They proposes that In vitro models are especially attractive in predictive toxicology as they can greatly reduce assay costs and animal usage while identifying those chemicals that may require further in vivo evaluation. This review covers various toxicological studies and strategies extensively those have been used with embryonic stem cells during last five years and possible directions that could lead to improvements in the development of predictive assays in future. Susana Inoges et al. have discussed the potential of autologous or allogeneic stem cell transplantation in treatment of B-cell malignancy including multiple myeloma and follicular lymphoma. They have discussed the clinical trials that combined stem cell transplant procedures with idiotypic vaccination, which also includes some of his experience with the transplant and his original data, as well as overall evaluation of this field of stem cell transplantation. Finally, he concluded that toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity in incurable B-cell malignancies. Present issue discusses in detail about the development of stem cell field, its potential uses and future directions to upcoming clinician and researchers.

Normal tissue homeostasis involves a careful balance between the normal cell loss and renewal. Stem and progenitor cells help maintain this precise and fine balance through their ability of self-renewal in a tightly regulated manner. In this regard, the gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The colonic crypt is primarily a proliferative compartment, is monoclonal and is maintained by stem cells. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue has led to the concept of a cellular hierarchy in tissues and in tumors including colorectal cancer (CRC). Thus, only a few cells may be necessary and sufficient for tissue repair or tumor regeneration. However, such a proposition also raises questions regarding the precise methods and markers to identify such population and to define the circumstantial evidences and place for the origin and establishment of the early mutant stem-cell population. Thus, it is imperative that we understand what cancer stem cells (CSC) are and their potential association with cancer in a tissue specific manner. In this review, we have summarized the current knowledge of stem cell organization and CSC within the colonic epithelium and discussed the potential role of CSC in the development and/or progression of CRC and as targets for therapeutic interventions.

Due to the recent advancements in stem cell biology and engineering, scientists have been increasingly interested in creating in vitro niches for embryonic and adult stem cells, and, following induction and differentiation with the appropriate media, the production of large scale blood production. This artificially created niche for hematopoietic cells will be composed of three materials: the stem cells themselves, the scaffold surrounding the stem cell, and the media used to expand and differentiate the stem cells. This paper will examine the recent advancements in technology for each of these relating to the development of an artificial stem cell niche. Many key aspects of the artificial niche need to be improved on before we can scale up the engineered device for large scale blood production including more efficient methods of retrieval of the embroid bodies produced from the microfluidic channels. The current state of experimental methods such as these as well as relevant discoveries in related fields that could be applied to artificial niche technology is described in this paper. Furthermore, we present a mathematical model to describe cell expansion in the artificial hematopoietic stem cell niche in order to design and optimize a scaled-up bioreactor. The mathematical model describes the dynamics of expansion, and maintenance of homeostasis in the bioreactor.

With advances in stem cell biology, tissue engineering is becoming increasingly powerful for tissue regeneration. Stem cells with capacity of multilineage and self-renewal are an ideal cell source for tissue engineering. This review focus on discussing the potential strategies including stem cell sources, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct ocular-lineage differentiation of stem cells for complete or partial eye regeneration and research. Attempts to use embryonic and somatic stem cells as seed cells for ocular tissue engineering have achieved encouraging results. The combination of chemical and physical signals in stem cell microenvironment could be regulated to induce differentiation of the embryonic stem cells into ocular tissue. This paper present here a broad introduction to the stem cell mediated correction of eye ailments and provide extensive references for the interested reader. This paper also looks into the different aspects of using stem cells for drug development for treating eye ailments.

Embryonic stem cells (ESC) can potentially be manipulated in vitro to differentiate into cells and tissues of all three germ layers. This pluripotent feature is being exploited to use ESC-derived tissues as therapies for degenerative diseases and replacement of damaged organs. Although their potential is great, the promise of ESC-derived therapies will be unfulfilled unless several challenges are overcome. For example, inefficient production of ESC-derived tissues before transplantation, inability of ESC-derived tissues to integrate well into the adult microenvironments due to developmental stage incompatibility, or active immune rejection of the ESC-derived graft are all potential challenges to successful ESCderived therapies. One way to induce immunological tolerance to allogeneic tissues is via the establishment of mixed hematopoietic chimerism in which the host and donor cells are educated to recognize each other as “self”. Proof of principle that in vitro cultured ESC-derived hematopoietic progenitors can be transplanted and induce immunological tolerance to allogeneic tissues exists in mouse models. In this review, we discuss the challenges to in vitro development of a bona fide ESC-derived hematopoietic stem cell and their differentiation fate in vivo, and provide suggestions to predict the immunogenicity of specific ESC-derived hematopoietic populations before transplantation that could be used to prevent their rejection after transplantation into an adult host.

Given the vast number of chemicals that are released into the environment each year, it is imperative that we develop new predictive models to identify toxicants before unavoidable exposure harms the health of humans and other organisms. In vitro models are especially attractive in predictive toxicology as they can greatly reduce assay costs and animal usage while identifying those chemicals that may require further in vivo evaluation. With the derivation of both mouse and human embryonic stem cells, new opportunities have developed that could revolutionize the field of predictive toxicology. Stem cells themselves can be used to model the earliest stages of development, or they can be differentiated to study later aspects of development. Because embryos and fetuses are usually more sensitive to environmental toxicants than adults, stem cells provide an unique tool for studying the prenatal phase in our life cycle. The embryonic stem cell test (EST), which has been validated for use with mouse embryonic stem cells (mESC), is an accurate predictor of embryotoxic compounds, particularly those that are highly embryotoxic. Human embryonic stem cells (hESCs), although not yet incorporated into a validated test, are a particularly attractive platform for toxicological testing as they can give us direct information on humans and avoid concerns about species variation in response. This review discusses toxicological studies and strategies that have been used with embryonic stem cells during the past five years and possible directions that could lead to improvements in the development of predictive assays in the future.

Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.

In this special issue of Current Topics in Medicinal Chemistry, the reader will find reviewed some of the hottest topics in the field of the non-reproductive effects of sex steroids. Cabrera-Munoz et al., show that progesterone participates in the regulation of human brain tumors growth. The contribution of Martocchia suggests that sex steroid receptor modulating drugs provide new therapeutic approaches to autoimmune diseases. The role of sex steroid participation in the differentiation of stem cells to neurones is discussed by I. Velasco. Perez-Torres and collaborators demonstrate that sex steroids play an important role in the appearance and development of renal diseases and the metabolic syndrome, the new epidemics of our century. Paris and Frye hypthetize that gestational stress, have effects on cognitive performance and/or neuronal integrity in the fetus, and that exposure to variable stress during gestation can perturb cognitive performance, concomitant with dendrite development in hippocampus and diencephalon. Munoz-Cruz et al. thoroughly review the growing body of evidence that shows reciprocal relationship between sex steroids and the immune system, and conclude that understanding the mechanisms of action of sex steroids on immune cells is important for further progress in the development of novel therapies for chronic diseases associated to immune dysregulation. Besides, the effects of sexual steroids on pancreatic function and diabetes are reviewed by Morimoto et al. Yanes et al. review some of the contradictions raised in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Finally, another vey intetresting aspect of the non-reproductive effects of sex-steroids, is the related to some cognition-related aspects, which is reviewed by Picazo et al.

Progesterone (P) participates in the regulation of several reproductive processes such as ovulation and sexual behavior, however, this hormone also participates in non-reproductive processes, such as neural excitability, learning and memory, and pathological processes such as cancer. P mainly elicits its effects by interaction with its intracellular receptor (PR), which is a ligand-activated transcription factor that modifies the expression of genes involved in the control of cell growth and proliferation, such as vascular endothelial growth factor and epidermal growth factor receptor. Two PR isoforms have been reported: PR-B and PR-A, which present different function and regulation. PR isoforms are expressed in U373 and D54 cell lines, which are derived from grades III and IV of human astrocytomas, respectively. In both cells lines P increases the number of astrocytomas cells. The PR antagonist, RU486, blocked P effects and its treatment alone significantly reduced human astrocytomas cell growth in vitro. The over-expression of PR-A in U373 cells significantly reduced P effects. These data suggest that P regulates human astrocytomas cell proliferation through the interaction with PR.

A sexual dymorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trials will help to find the best use of sex steroids in combination with current therapeutic drugs in autoimmune diseases. Sex steroid receptor modulating drugs will provide new therapeutic approaches in these pathologies.

Pluripotent and multipotent stem cells with differentiation potential to neural phenotypes have been described and characterized in the last decades. Embryonic stem cells, as well as neural stem cells from developing and adult nervous system, can differentiate into different types of neurons, astrocytes or oligodendrocytes. Although the initially identified actions of estradiol, progesterone and testoterone are related to sexual reproductive functions, recent evidence shows that these steroid hormones modulate development, physiology and survival of nerve cells. Furthermore, neurosteroids can be synthesized in the developing and adult nervous system. A description of the molecular modulatory actions of sex steroid hormones on the Central Nervous System is presented. The main focus of this review is to summarize the described effects of steroid hormones (progesterone, allopregnanolone, dehydroepiandrosterone, estradiol and androgens) on cell parameters relevant to stem cells, both in vitro and in vivo. The overall conclusion is that steroid hormones influence stem cell behavior by several mechanisms, namely regulation of gene expression by binding to their cognate receptors, activation of intracellular pathways involving kinases or intracellular calcium signaling, and modulation of receptors for neurotransmitters; in some instances, these hormones can substitute or modulate the action of growth factors, and also directly influence self-renewal, proliferation, differentiation or cell death of neurogenic stem cells.

In the metabolic syndrome (MS), a condition that associates three or more pathologies such as hypertension, central obesity, type II diabetes, insulin resistance and dyslipidemias, the kidneys are severely affected. The pathological alterations in the kidneys, associated with MS, may be modified by sex hormone levels. In general, estrogens are a protection against the development of cardiovascular and renal diseases in humans and experimental models, but androgens may have an opposite effect. Among the metabolic systems that can be modulated by sex hormones in the kidney, the more important are: renin-angiotensin-aldosterone system, arachidonic acid metabolism, nitric oxide system and renal extracellular matrix proteins. These are metabolic pathways normally associated, in order to maintain the most efficient functioning of renal hemodynamics. There is a close interrelationship between sex hormones and some pathways involved in the metabolic syndrome; also pathways can modulate each other. The circulating concentrations of hormones may determine the degree of overall pathological alterations in the syndrome.

Gestational stress may have lasting deleterious effects on neuro-cognitive development of offspring. Progesterone (P), and its 5α-reduced metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP), maintain pregnancy, and can have effects on cognitive performance and/or neuronal integrity. However, whether some of the deleterious effects of gestational stress on cognitive and neural processes may be related to progestogen formation is not known. Pregnant rat dams were exposed to a regimen of variable stressors (including forced swim, restraint, fasting, social stress, and exposure to cold and light) on gestational days 17-21 or were minimally-handled controls. Male and female offspring were cross-fostered to non-manipulated dams and assessed for motor and cognitive performance between postnatal days 28 and 30. Although the motor behavior of gestationally-stressed offspring did not differ significantly from control, offspring, their cognitive performance in an object recognition task was poorer. Irrespective of sex, dendritic spine density was reduced in dorsal hippocampus of stress-exposed offspring compared to control offspring. Formation of DHP was reduced in medial prefrontal cortex (mPFC) and increased in hippocampus of stressed, compared to control, offspring. Notably, there were sex differences wherein estradiol in mPFC, as well as P and DHP in diencephalon, were increased with stress among females but decreased with stress among males. These data suggest that exposure to variable stress during gestation can perturb cognitive performance, concomitant with dendrite development in hippocampus, and P's 5α-reduction in hippocampus and mPFC. Some sex differences in stress effects on progestogen formation may occur in diencephalon.

Sex hormones play an important role as modulators of the immune system. A growing body of evidence shows reciprocal relationship between sex steroids and the immune system. Since the innate immune response determines the type of adaptive immune response, hormonal effects on the innate immune response may affect subsequent adaptive immunity. The sex steroids estrogens, progesterone and testosterone regulate growth, differentiation, survival and function of many cell types involved in homeostasis and immunity. The presence of sex steroid receptors on immune cells indicates that sex steroids may exert their biological effects by binding to these receptors. Sex steroids and immunity are closely connected, and their mutual regulation is involved in the maintenance of immune balance. Understanding the mechanisms of action of sex steroids on immune cells is important for further progress in the development of novel therapies for chronic diseases associated to immune dysregulation. This review describes the effects of sex steroids on the different immune system cells, and the possible implications of these effects on the incidence of many diseases

Traditionally the role of sexual steroid hormones was focused primarily on reproductive organs: the breast, female reproductive tract (uterus, mammary gland, and ovary), and male reproductive tract (testes, epididymis and prostate), however our current understanding of tissue-specific effects of sex steroids has elucidated new aspects in its functionality. Recent data have shown that many other tissues are targets of those hormones in addition to classical reproductive organs. The pancreas (which performs both endocrine and exocrine functions), has proven to be an extragonadal target of sexual steroid hormone action. The endocrine pancreas has a pivotal role on carbohydrate homeostasis and deterioration in function produces diabetes. Diabetes is a metabolic disorder that has high prevalence worldwide, particularly in developing countries. It has been shown that steroid hormones have an important role in susceptibility and development of diabetes in animal models, in humans its role is less clear, however the most evident effect is on the perimenopausal women, in this stage the decrease in gonadal steroids produces an increase on susceptibility to develop diabetes mellitus; in men, hypoandrogenism is associated with an increased prevalence of insulin resistance. This review focused on the effects of sexual steroids on pancreatic function and diabetes.

Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism( s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk factors, such as dyslipidemias, visceral obesity and endothelial dysfunction. Recently it became apparent that in a large number of hypertensive postmenopausal women, their BP is not well controlled with conventional antihypertensive medications. A clear understanding of the complex pathogenesis of postmenopausal hypertension is needed in order to offer the best therapeutic options for these women.

Two of the most studied brain areas related with learning and memory are prefrontal cortex and hippocampus. However, serious inconsistencies arise when these regions are analyzed in relation to the role of estrogens on cognitive deterioration. Some of these contradictions are reviewed in the context of the recently proposed critical period hypothesis, which takes into account the frame-time after cessation of ovarian function. Other factors related with cognition and influenced by estrogens include their role on; a) cholinergic central transmission, b) spinogenesis and synaptogenesis at hippocampus, and c) classical genomic and rapid non genomic effects. Understanding the cellular and molecular basis of these phenomena is vital for designing novel therapeutic actions applicable to human health and disease.