Adult stem cells: Simply a tool for regenerative medicine or an additional piece in the puzzle of human aging?

Adult stem cells have taken center stage in current research related to regenerative medicine and pharmacogenomic studies seeking new therapeutic interventions. As we learn more about these cells, it is becoming apparent that the next big leap in our understanding of adult stem cell biology and adult stem cell aging will depend on the integration of approaches from various disciplines. Major advances and technological breakthroughs at the crossroad of fields such as biomaterials, genomics, epigenomics, and proteomics will enable the design of better tools to model human diseases, and warrant safe usage of adult stem cells in the clinic.     

The osteocyte

Osteocytes are the most numerous cells in mature bone and have the potential to live as long as the organism itself. However, study and subsequent understanding of osteocyte biology has been thwarted by the remote location of the cell in the mineralized matrix. This review is intended to synthesize current understanding of osteocyte biology and to suggest future paths that will promote understanding of this obscure cell and translation of knowledge to disease prophylaxis and management.     

Microbial gene expression in soil: methods, applications and challenges

About 99% of soil microorganisms are unculturable. However, advances in molecular biology techniques allow for the analysis of living microorganisms. With the advent of new technologies and the optimization of previous methods, various approaches to studying gene expression are expanding the field of microbiology and molecular biology. Methods used for RNA extraction, DNA microarrays, real-time PCR, competitive RT-PCR, stable isotope probing and the use of reporter genes provide methods for detecting and quantifying gene expression. Through the use of these methods, researchers can study the influence of soil environmental factors such as nutrients, oxygen status, pH, pollutants, agro-chemicals, moisture and temperature on gene expression and some of the mechanisms involved in the responses of cells to their environment. This review will also address information gaps in bacterial gene expression in soil and possible future research to develop an understanding of microbial activities in soil environments.     

Understanding cornea epithelial stem cells and stem cell deficiency: Lessons learned using vertebrate model systems

Animal models have contributed greatly to our understanding of human diseases. Here, we focus on cornea epithelial stem cell (CESC) deficiency (commonly called limbal stem cell deficiency, LSCD). Corneal development, homeostasis and wound healing are supported by specific stem cells, that include the CESCs. Damage to or loss of these cells results in blindness and other debilitating ocular conditions. Here we describe the contributions from several vertebrate models toward understanding CESCs and LSCD treatments. These include both mammalian models, as well as two aquatic models, Zebrafish and the amphibian, Xenopus. Pioneering developments have been made using stem cell transplants to restore normal vision in patients with LSCD, but questions still remain about the basic biology of CESCs, including their precise cell lineages and behavior in the cornea. We describe various cell lineage tracing studies to follow their patterns of division, and the fates of their progeny during development, homeostasis, and wound healing. In addition, we present some preliminary results using the Xenopus model system. Ultimately, a more thorough understanding of these cornea cells will advance our knowledge of stem cell biology and lead to better cornea disease therapeutics.     

SP analysis may be used to identify cancer stem cell populations

Side populations (SP), as defined by Hoechst exclusion in flow cytometry, have been described a few years ago. While they represent only a small fraction of the whole cell population, their properties confer an important place in several investigations. SP cells express high levels of various members of ABC transporters family, such as MDR1 and BCRP, which are responsible for drug resistance. Targeting SP could improve cancer therapy by blocking these transporters. In addition, SP appear to be enriched in stem cells, cells that play a pivotal role in normal development and cancer biology. Thus, they could provide a useful tool and a readily accessible source for stem cell studies in both the normal and cancerous settings. However, these cells are poorly defined and pose challenges in their identification and isolation, particularly since they are few in number. Thus, better characterization of SP will advance our understanding of stem cells and will provide us an accessible target for drug resistance in cancer therapy.     

The osteoclast: a multinucleated, hematopoietic-origin, bone-resorbing osteoimmune cell

Osteoclasts are multinucleated cells that derive from hematopoietic progenitors in the bone marrow which also give rise to monocytes in peripheral blood, and to the various types of tissue macrophages. Osteoclasts are formed by the fusion of precursor cells. They function in bone resorption and are therefore critical for normal skeletal development (growth and modeling), for the maintenance of its integrity throughout life, and for calcium metabolism (remodeling). To resorb bone, the osteoclasts attach to the bone matrix, their cytoskeleton reorganizes, and they assume polarized morphology and form ruffled borders to secrete acid and collagenolytic enzymes and a sealing zone to isolate the resorption site. Identification of the osteoclastogenesis inducer, the receptor activator of nuclear factor-kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG), has contributed enormously to the dramatic advance in our understanding of the molecular mechanisms involved in osteoclast differentiation and activity. This explosion in osteoclast biology is reflected by the large number of reviews which appeared during the last decade. Here I will summarize the "classical" issues (origin, differentiation, and activity) in a general manner, and will discuss an untouched issue (multinucleation) and a relatively novel aspect of osteoclast biology (osteoimmunology).     

Proteomics of membrane receptors and signaling

Receptors represent an abundant class of integral membrane proteins that transmit information on various types of signals within the cell. Assemblages of receptors and their interacting proteins (receptor complexes) have emerged as important units of signal transduction for various types of receptors including G protein coupled, ligand-gated ion channel, and receptor tyrosine kinase. This review aims to summarize the major approaches and findings of receptor proteomics. Isolation and characterization of receptor complexes from cells has become common using the methods of immunoaffinity-, ligand-, and tag-based chromatography followed by MS for the analysis of enriched receptor preparations. In addition, tools such as stable isotope labeling have contributed to understanding quantitative properties and PTMs to receptors and their interacting proteins. As data from studies on receptor-protein interactions considerably expands, complementary approaches such as bioinformatics and computational biology will undoubtedly play a significant role in defining cellular and network functions for various types of receptor complexes. Findings from receptor proteomics may also shed light on the mechanism of action for pharmacological drugs and can be of value in understanding molecular pathologies of disease states.     

Evolutionarily conserved concepts in glial cell biology

The evolutionary conservation of glial cells has been appreciated since Ramon y Cajal and Del Rio Hortega first described the morphological features of cells in the nervous system. We now appreciate that glial cells have essential roles throughout life in most nervous systems. The field of glial cell biology has grown exponentially in the last ten years. This new wealth of knowledge has been aided by seminal findings in non-mammalian model systems. Ultimately, such concepts help us to understand glia in mammalian nervous systems. Rather than summarizing the field of glial biology, I will first briefly introduce glia in non-mammalian models systems. Then, highlight seminal findings across the glial field that utilized non-mammalian model systems to advance our understanding of the mammalian nervous system. Finally, I will call attention to some recent findings that introduce new questions about glial cell biology that will be investigated for years to come.     

A molecular view of stem cell and cancer cell self-renewal

With the recent advances in cell biology and molecular genetics, scientists were able to isolate and culture tissue-specific stem cells from various sources and define their properties. The challenge has now shifted to understanding the genetic programs controlling the stem cell state, i.e. self-renewal and multipotential. Cracking the molecular codes that govern the stem cell state turns out to be a difficult task. This is in part because a single gene may exhibit distinct activities when expressed in different cell types. Comprehending the cell-context dependent readout of any given gene requires an integrated knowledge of the complex cellular machinery, a platform which can be provided by the research on stem cells. This review is an attempt to formulate a model for the self-renewal machinery operating in stem cells and cancer cells. Insight into this issue at the molecular and cellular levels will no doubt facilitate the realization of the stem cell potential in both regenerative medicine and anticancer therapy.     

Mesenchymal stem cells in arthritic diseases

Mesenchymal stem cells (MSCs), the nonhematopoietic progenitor cells found in various adult tissues, are characterized by their ease of isolation and their rapid growth in vitro while maintaining their differentiation potential, allowing for extensive culture expansion to obtain large quantities suitable for therapeutic use. These properties make MSCs an ideal candidate cell type as building blocks for tissue engineering efforts to regenerate replacement tissues and repair damaged structures as encountered in various arthritic conditions. Osteoarthritis (OA) is the most common arthritic condition and, like rheumatoid arthritis (RA), presents an inflammatory environment with immunological involvement and this has been an enduring obstacle that can potentially limit the use of cartilage tissue engineering. Recent advances in our understanding of the functions of MSCs have shown that MSCs also possess potent immunosuppression and anti-inflammation effects. In addition, through secretion of various soluble factors, MSCs can influence the local tissue environment and exert protective effects with an end result of effectively stimulating regeneration in situ. This function of MSCs can be exploited for their therapeutic application in degenerative joint diseases such as RA and OA. This review surveys the advances made in the past decade which have led to our current understanding of stem cell biology as relevant to diseases of the joint. The potential involvement of MSCs in the pathophysiology of degenerative joint diseases will also be discussed. Specifically, we will explore the potential of MSC-based cell therapy of OA and RA by means of functional replacement of damaged cartilage via tissue engineering as well as their anti-inflammatory and immunosuppressive activities.     

Spermatogonial stem cells, infertility and testicular cancer

The spermatogonial stem cells (SSCs) are responsible for the transmission of genetic information from an individual to the next generation. SSCs play critical roles in understanding the basic reproductive biology of gametes and treatments of human infertility. SSCs not only maintain normal spermatogenesis, but also sustain fertility by critically balancing both SSC self-renewal and differentiation. This self-renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression within the SSC as well as the extrinsic gene signals from the niche. Increased SSCs self-renewal at the expense of differentiation result in germ cell tumours, on the other hand, higher differentiation at the expense of self-renewal can result in male sterility. Testicular germ cell cancers are the most frequent cancers among young men in industrialized countries. However, understanding the pathogenesis of testis cancer has been difficult because it is formed during foetal development. Recent studies suggest that SSCs can be reprogrammed to become embryonic stem (ES)-like cells to acquire pluripotency. In the present review, we summarize the recent developments in SSCs biology and role of SSC in testicular cancer. We believe that studying the biology of SSCs will not only provide better understanding of stem cell regulation in the testis, but eventually will also be a novel target for male infertility and testicular cancers.     

Molecular biology in biorheology

This presentation is aimed at giving some background information on molecular biology, thus serving as an introduction to the Symposium on Molecular Biorheology held during the Sixth International Congress of Biorheology in Vancouver. The papers presented at this Symposium indicate that the use of molecular biological techniques allows the understanding of normal and abnormal rheological properties of cells and organs at the molecular level. It is hoped that these examples will provide an impetus for us to open new frontiers of research in biorheology by taking advantage of the powerful tools developed from recent advances in molecular biology.     

Strategies for organ level tissue engineering

The field of tissue engineering has made considerable strides since it was first described in the late 1980s. The advent and subsequent boom in stem cell biology, emergence of novel technologies for biomaterial development, and further understanding of developmental biology have contributed to this accelerated progress. However, continued efforts to translate tissue engineering strategies into clinical therapies have been hampered by the problems associated with scaling up laboratory methods to produce large, complex tissues. The significant challenges faced by tissue engineers include the production of an intact vasculature within a tissue-engineered construct and recapitulation of the size and complexity of a whole organ. Here we review the basic components necessary for bioengineering organs – biomaterials, cells and bioactive molecules–and discuss various approaches for augmenting these principles to achieve organ level tissue engineering. Ultimately, the successful translation of tissue-engineered constructs into everyday clinical practice will depend upon the ability of the tissue engineer to “scale up” every aspect of the research and development process.     

How do tumor stem cells actively escape from host immunosurveillance?

Tumor stem cells (TSCs) are considered as the "seeds" in tumor development, metastasis and recurrence. Despite the various immunosurveillance mechanisms in the host, TSCs may possess the phenotypic and functional properties to evade host immunosurveillance and immune-mediated rejection in immunologically intact individuals. The mechanisms of TSC recognition and their consequent destruction are actively disturbed by various processes, including altered immunogenicity of TSCs, production of TSC-derived regulatory molecules, and interaction of TSCs with tumor-infiltrating immune cells. In addition to these TSC-mediated mechanisms, the diverse mesenchymal cells and cytokines in the tumor microenvironment are contribute to TSC immune escape. Recent mechanistic studies provide a more comprehensive understanding of TSCs in the biology, prevention, and therapy of solid tumors. This review will focus on the latest findings for mechanisms underlying TSCs' escape from the attack of immune system.     

Regenerative cell therapy and pharmacotherapeutic intervention in heart failure

It has been postulated that bone marrow derived endothelial progenitor cells (BM-EPCs) are essential for neovascularisation and endothelial repair and are involved in pharmacological treatment, and even its potential targets. There is no doubt that the ultimate success of angiogenic cell therapy will be determined by an appropriate stimulation of certain angiogenic progenitor cell subpopulations. Unfortunately, the biology of EPCs is still poorly understood. In particular, the understanding of endogenous microenvironments within the progenitor cell niches is critical, and will provide us with information about the signalling systems that supply a basis to develop rational pharmacotherapy to enhance the functional activity of endogenous or transplanted progenitor cells. The final success of clinical improvement of progenitor cell-mediated vascular repair and angiogenic therapy depends on a better understanding of EPC biology and a smart therapeutic design. In the first part of this review we first briefly discuss the possible involvement of progenitor cells in chronic heart failure. In part 2 we focus on factors that beneficially affect BMEPCs, with an emphasis on pharmacological molecular pathways involved in BM-EPC-induced neovascularisation. (Neth Heart J 2008;16:305-9.)     

Strategies for organ level tissue engineering

The field of tissue engineering has made considerable strides since it was first described in the late 1980s. The advent and subsequent boom in stem cell biology, emergence of novel technologies for biomaterial development and further understanding of developmental biology have contributed to this accelerated progress. However, continued efforts to translate tissue-engineering strategies into clinical therapies have been hampered by the problems associated with scaling up laboratory methods to produce large, complex tissues. The significant challenges faced by tissue engineers include the production of an intact vasculature within a tissue-engineered construct and recapitulation of the size and complexity of a whole organ. Here we review the basic components necessary for bioengineering organs-biomaterials, cells and bioactive molecules-and discuss various approaches for augmenting these principles to achieve organ level tissue engineering. Ultimately, the successful translation of tissue-engineered constructs into everyday clinical practice will depend upon the ability of the tissue engineer to "scale up" every aspect of the research and development process.     

Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy

Tumor cells utilize different strategies to communicate with neighboring tissues for facilitating tumor progression and invasion, one of these strategies has been shown to be the release of exosomes. Exosomes are small nanovesicles secreted by all kind of cells in the body, especially cancer cells, and mediate cell to cell communications. Exosomes play an important role in cancer invasiveness by harboring various cargoes that could accelerate angiogenesis. Here first, we will present an overview of exosomes, their biology, and their function in the body. Then, we will focus on exosomes derived from tumor cells as tumor angiogenesis mediators with a particular emphasis on the underlying mechanisms in various cancer origins. Also, exosomes derived from stem cells and tumor-associated macrophages will be discussed in this regard. Finally, we will discuss the novel therapeutic strategies of exosomes as drug delivery vehicles against angiogenesis.     

Functional screening revisited in the postgenomic era

Functional screening can reveal a hidden function of a gene. cDNA library-based functional screening has flourished in various fields of biology so far, such as cancer biology, developmental biology and neuroscience. In the postgenomic era, however, various sequence database and public full-length cDNA resources are available, which now allow us to perform more straightforward, gene-oriented screening. Furthermore, the advent of RNA interference techniques has made it possible to perform effective loss-of-function screening. Gene-based functional screening is able to bridge the gap between genes and biological phenomena and raise important biological questions which should be tackled by integration of 'omic' datasets. These possible roles of functional screening will become more and more important in modern molecular biology moving toward the system level understanding of living organisms.     

Laws of biology: why so few?

Finding fundamental organizing principles is the current intellectual front end of systems biology. From a hydrogen atom to the whole cell level, organisms manage massively parallel and massively interactive processes over several orders of magnitude of size. To manage this scale of informational complexity it is natural to expect organizing principles that determine higher order behavior. Currently, there are only hints of such organizing principles but no absolute evidences. Here, we present an approach as old as Mendel that could help uncover fundamental organizing principles in biology. Our approach essentially consists of identifying constants at various levels and weaving them into a hierarchical chassis. As we identify and organize constants, from pair-wise interactions to networks, our understanding of the fundamental principles in biology will improve, leading to a theory in biology.     

Unraveling the molecular components and genetic blueprints of stem cells

Remarkable progress in stem cell biology research over the past few years has provoked a promise for the future of tissue regeneration and gene therapies; so much so, that the use of stem cells in clinical therapy seemed to be just around the corner. However, we now realize there is still a huge task before us to improve our understanding of the nature of stem cells before utilizing them to benefit human health. Stem cell behavior is determined by specific gene products; thus, unraveling the molecular components and genetic blueprints of stem cells will provide important insight into understanding stem cell properties. Here we summarize the research of various groups using microarray technology and other approaches to determine the gene expression profiles in stem cells, particularly in hematopoietic stem cells (HSCs). These works have, to a certain degree, helped to narrow down the candidate genes predominantly expressed in HSCs, revealed a list of stemness genes, and indirectly demonstrated the wide-open chromatin state of stem cells and, with it, the molecular basis of the multipotentiality of stem cells.