Mesenchymal stem cells: biological characteristics and potential clinical applications

Mesenchymal stem cells (MSC) are clonogenic, non-hematpoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages, for example, osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages, for example, neuronal-like cells. Several methods are currently available for isolation of the MSC based on their physical and physico-chemical characteristics, for example, adherence to plastics or other extracellular matrix components. Because of the ease of their isolation and their extensive differentiation potential, MSC are among the first stem cell types to be introduced in the clinic. Several studies have demonstrated the possible use of MSC in systemic transplantation for systemic diseases, local implantation for local tissue defects, as a vehicle for genes in gene therapy protocols or to generate transplantable tissues and organs in tissue engineering protocols. Before their widespread use in therapy, methods allowing the generation of large number of cells without affecting their differentiation potential as well as technologies that overcome immunological rejection (in case allogenic transplantation) must be developed.     

Cell adhesion and mechanical stimulation in the regulation of mesenchymal stem cell differentiation

Stem cells have been shown to have the potential to provide a source of cells for applications to tissue engineering and organ repair. The mechanisms that regulate stem cell fate, however, mostly remain unclear. Mesenchymal stem cells (MSCs) are multipotent progenitor cells that are isolated from bone marrow and other adult tissues, and can be differentiated into multiple cell lineages, such as bone, cartilage, fat, muscles and neurons. Although previous studies have focused intensively on the effects of chemical signals that regulate MSC commitment, the effects of physical/mechanical cues of the microenvironment on MSC fate determination have long been neglected. However, several studies provided evidence that mechanical signals, both direct and indirect, played important roles in regulating a stem cell fate. In this review, we summarize a number of recent studies on how cell adhesion and mechanical cues influence the differentiation of MSCs into specific lineages. Understanding how chemical and mechanical cues in the microenvironment orchestrate stem cell differentiation may provide new insights into ways to improve our techniques in cell therapy and organ repair.     

Patterns of cell division and the risk of cancer

Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.     

0Adipose-derived stem cells: Implications in tissue regeneration

Adipose-derived stem cells(ASCs) are mesenchymal stem cells(MSCs) that are obtained from abundant adipose tissue, adherent on plastic culture flasks, can be expanded in vitro, and have the capacity to differ-entiate into multiple cell lineages. Unlike bone marrow-derived MSCs, ASCs can be obtained from abundant adipose tissue by a minimally invasive procedure, which results in a high number of cells. Therefore, ASCs are promising for regenerating tissues and organs dam-aged by injury and diseases. This article reviews the implications of ASCs in tissue regeneration.     

Epigenetic regulation in adult stem cells and cancers

Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells.     

Mouse chimeras as a system to investigate development,cell and tissue function,disease mechanisms and organ regeneration

Chimeras are organisms composed of at least two genetically distinct cell lineages originating from different zygotes. In the laboratory, mouse chimeras can be produced experimentally; various techniques allow combining different early stage mouse embryos with each other or with pluripotent stem cells. Identification of the progeny of the different lineages in chimeras permits to follow cell fate and function, enabling correlation of genotype with phenotype. Mouse chimeras have become a tool to investigate critical developmental processes, including cell specification, differentiation, patterning and the function of specific genes. In addition, chimeras can also be generated to address biological processes in the adult, including mechanisms underlying diseases or tissue repair and regeneration. This review summarizes the different types of chimeras and how they have been generated and provides examples of how mouse chimeras offer a unique and powerful system to investigate questions pertaining to cell and tissue function in the developing and adult organism.Key words: chimera, developmental chimera, aggregation, blastocyst injection, embryonic stem cells, induced pluripotent stem cells, complementation, regeneration     

Diversification of haematopoietic stem cells to specific lineages

Diverse types of blood cell (lineages) are produced from rare haematopoietic stem cells that reside in the bone marrow. This process, known as haematopoiesis, provides a valuable model for examining how genetic programs are established and executed in vertebrates, and also how homeostasis of blood formation is altered in leukaemias. So, how does an apparently small group of critical lineage-restricted nuclear regulatory factors specify the diversity of haematopoietic cells? Recent findings not only indicate how this may be achieved but also show the extraordinary plasticity of tissue stem cells in vivo.     

Current issues and regulations in tendon regeneration and musculoskeletal repair with mesenchymal stem cells

Mesenchymal stem cells are multipotent stromal cells residing within the connective tissue of most organs. Their surface phenotype has been well described. Most commonly, mesenchymal stem cells demonstrate the ability to differentiate into mesenchymal tissues (bone, catailge, fat, etc...), however, under the proper conditions these cells can differentiate into epithelial cells and neuroectoderm derived lineages. Their developmental plasticity also depends on the ability of mesenchymal stem cells to alter the tissue microenvironment by secreting soluble factors, as well as their capacity for differentiation in tissue repair. It is the cell-matrix interaction which defines the tissue characteristics. The molecular and functional heterogeneity of this cell population may confound interpretation of their differentiation potential, but it is this heterogeneity that is believed to provide for their therapeutic efficacy. Stem cell therapies are an attractive therapeutic approach for soft tissues as they offer a vehicle for repair and regeneration at the end of a needle. The early introduction of stem cell treatments into the therapeutic armamentarium involves both commercial and non-commercial multidisciplinary partnerships and has occurred in a climate of regulatory reform, so not all the relevant information resides in the public domain, but early clinical studies have shown promising results. Against this backdrop, novel techniques and early results of a small series of tendon and musculotendinous junction interventions are being published and other ongoing studies are yet to report their results. The issue of ensuring governance of these novel technologies falls upon both the scientific community and the established licensing authorities.     

Adipose-derived stem cells: Implications in tissue regeneration

Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that are obtained from abundant adipose tissue, adherent on plastic culture flasks, can be expanded in vitro, and have the capacity to differentiate into multiple cell lineages. Unlike bone marrow-derived MSCs, ASCs can be obtained from abundant adipose tissue by a minimally invasive procedure, which results in a high number of cells. Therefore, ASCs are promising for regenerating tissues and organs damaged by injury and diseases. This article reviews the implications of ASCs in tissue regeneration.     

Mouse chimeras as a system to investigate development,cell and tissue function,disease mechanisms and organ regeneration

Chimeras are organisms composed of at least two genetically distinct cell lineages originating from different zygotes. In the laboratory, mouse chimeras can be produced experimentally; various techniques allow combining different early stage mouse embryos with each other or with pluripotent stem cells. Identification of the progeny of the different lineages in chimeras permits to follow cell fate and function, enabling correlation of genotype with phenotype. Mouse chimeras have become a tool to investigate critical developmental processes, including cell specification, differentiation, patterning, and the function of specific genes. In addition, chimeras can also be generated to address biological processes in the adult, including mechanisms underlying diseases or tissue repair and regeneration. This review summarizes the different types of chimeras and how they have been generated and provides examples of how mouse chimeras offer a unique and powerful system to investigate questions pertaining to cell and tissue function in the developing and adult organism.     

Stem cell-based composite tissue constructs for regenerative medicine

A major task of contemporary medicine and dentistry is restoration of human tissues and organs lost to diseases and trauma. A decade-long intense effort in tissue engineering has provided the proof of concept for cell-based replacement of a number of individual tissues such as the skin, cartilage, and bone. Recent work in stem cell-based in vivo restoration of multiple tissue phenotypes by composite tissue constructs such as osteochondral and fibro-osseous grafts has demonstrated probable clues for bioengineered replacement of complex anatomical structures consisting of multiple cell lineages such as the synovial joint condyle, tendon-bone complex, bone-ligament junction, and the periodontium. Of greater significance is a tangible contribution by current attempts to restore the structure and function of multitissue structures using cell-based composite tissue constructs to the understanding of ultimate biological restoration of complex organs such as the kidney or liver. The present review focuses on recent advances in stem cell-based composite tissue constructs and attempts to outline challenges for the manipulation of stem cells in tailored biomaterials in alignment with approaches potentially utilizable in regenerative medicine of human tissues and organs.     

The application of stem cells in the treatment of ischemic diseases

Ischemia causes oxygen deprivation, cell injury and related organ dysfunction. Although ischemic injury may be local, it involves many biochemical changes in different cell types. The ability of stem cells to differentiate into different cell lineages provides the possibility of their use in treating a variety of diseases requiring tissue repair or reconstitution, such as stroke, ischemic retinopathy, myocardial infarction, ischemic disorders of the liver, ischemic renal failure, and ischemic limb dysfunction. Several cell types including embryonic stem cells, various progenitor and stem cells of hematopoietic or mesenchymal origin have been used in attempts to reconstitute injured tissue. Xenologous or autologous stem cells may be administered either through the peripheral vascular system or directly by regional injection. The stem cells are then guided to the infarct site by homing signals. Either by cell differentiation or paracrine effects, stem cells or progenitor cells participate in the reconstruction of a favorable microenvironment resulting in neovascularization and tissue regeneration that eventually improve the physiological function of organs with ischemic damage.     

Phyllotactic pattern and stem cell fate are determined by the Arabidopsis homeobox gene BELLRINGER

Lateral organs in plants arise from the meristem in a stereotypical pattern known as phyllotaxy. Spiral patterns result from initiation of successive organs at a fixed angle of divergence but variable patterns of physical contact. Such patterns ultimately give rise to individual leaves and flowers at positions related to each other by consecutive terms in the mathematical series first described by Leonardo Fibonacci. We demonstrate that a BELL1 related homeodomain protein in Arabidopsis, BELLRINGER, maintains the spiral phyllotactic pattern. In the absence of BELLRINGER, the regular pattern of organ initiation is disturbed and lateral organs are initiated more frequently. BELLRINGER is also required for maintenance of stem cell fate in the absence of the regulatory genes SHOOT MERISTEMLESS and ASYMMETRIC LEAVES1. We propose a model whereby BELLRINGER coordinates the maintenance of stem cells with differentiation of daughter cells in stem cell lineages.     

Stochastic Dynamics of Interacting Haematopoietic Stem Cell Niche Lineages

Since we still know very little about stem cells in their natural environment, it is useful to explore their dynamics through modelling and simulation, as well as experimentally. Most models of stem cell systems are based on deterministic differential equations that ignore the natural heterogeneity of stem cell populations. This is not appropriate at the level of individual cells and niches, when randomness is more likely to affect dynamics. In this paper, we introduce a fast stochastic method for simulating a metapopulation of stem cell niche lineages, that is, many sub-populations that together form a heterogeneous metapopulation, over time. By selecting the common limiting timestep, our method ensures that the entire metapopulation is simulated synchronously. This is important, as it allows us to introduce interactions between separate niche lineages, which would otherwise be impossible. We expand our method to enable the coupling of many lineages into niche groups, where differentiated cells are pooled within each niche group. Using this method, we explore the dynamics of the haematopoietic system from a demand control system perspective. We find that coupling together niche lineages allows the organism to regulate blood cell numbers as closely as possible to the homeostatic optimum. Furthermore, coupled lineages respond better than uncoupled ones to random perturbations, here the loss of some myeloid cells. This could imply that it is advantageous for an organism to connect together its niche lineages into groups. Our results suggest that a potential fruitful empirical direction will be to understand how stem cell descendants communicate with the niche and how cancer may arise as a result of a failure of such communication.     

Using polymeric materials to control stem cell behavior for tissue regeneration

Patients with organ failure often suffer from increased morbidity and decreased quality of life. Current strategies of treating organ failure have limitations, including shortage of donor organs, low efficiency of grafts, and immunological problems. Tissue engineering emerged about two decades ago as a strategy to restore organ function with a living, functional engineered substitute. However, the ability to engineer a functional organ is limited by a limited understanding of the interactions between materials and cells that are required to yield functional tissue equivalents. Polymeric materials are one of the most promising classes of materials for use in tissue engineering, due to their biodegradability, flexibility in processing and property design, and the potential to use polymer properties to control cell function. Stem cells offer potential in tissue engineering because of their unique capacity to self‐renew and differentiate into neurogenic, osteogenic, chondrogenic, and myogenic lineages under appropriate stimuli from extracellular components. This review examines recent advances in stem cell–polymer interactions for tissue regeneration, specifically highlighting control of polymer properties to direct adhesion, proliferation, and differentiation of stem cells, and how biomaterials can be designed to provide some of the stimuli to cells that the natural extracellular matrix does. (Part C) 96:63–81, 2012. © 2012 Wiley Periodicals, Inc.     

The gastrointestinal stem cell

The longevity of adult stem cells, and their potential for vast tissue regeneration, makes them a focal point of current research and debate, with future aspirations for the use of stem cells in the treatment of a number of human pathological conditions. Due to the rapid rate of cell turnover in the gastrointestinal tract, the stem cells of this tissue are amongst the most assiduous in the body, although they remain unidentified to this day due to their immature, undifferentiated phenotype. However, our knowledge of the mechanisms regulating gastrointestinal stem cell function is evolving, with the identification of putative cellular markers and the elucidation of signalling pathways which regulate cell behaviour in the normal and neoplastic gastrointestinal tract. This review describes the fundamental properties of the gastrointestinal stem cell including: (i) their number, location and origins, (ii) their primary function of deriving gastrointestinal cell lineages and maintaining tissue homeostasis, (iii) the acquisition of gastrointestinal cell lineages from adult stem cells of extraneous tissues and the consequences of this in a therapeutic context, and (iv) the genetic and morphological phenomena surrounding neoplastic transformation in the gastrointestinal tract.     

Stem cells: their source,potency and use in regenerative therapies with focus on adipose-derived stem cells – a review

Stem cells can be defined as units of biological organization that are responsible for the development and the regeneration of organ and tissue systems. They are able to renew their populations and to differentiate into multiple cell lineages. Therefore, these cells have great potential in advanced tissue engineering and cell therapies. When seeded on synthetic or nature-derived scaffolds in vitro, stem cells can be differentiated towards the desired phenotype by an appropriate composition, by an appropriate architecture, and by appropriate physicochemical and mechanical properties of the scaffolds, particularly if the scaffold properties are combined with a suitable composition of cell culture media, and with suitable mechanical, electrical or magnetic stimulation. For cell therapy, stem cells can be injected directly into damaged tissues and organs in vivo. Since the regenerative effect of stem cells is based mainly on the autocrine production of growth factors, immunomodulators and other bioactive molecules stored in extracellular vesicles, these structures can be isolated and used instead of cells for a novel therapeutic approach called “stem cell-based cell-free therapy”. There are four main sources of stem cells, i.e. embryonic tissues, fetal tissues, adult tissues and differentiated somatic cells after they have been genetically reprogrammed, which are referred to as induced pluripotent stem cells (iPSCs). Although adult stem cells have lower potency than the other three stem cell types, i.e. they are capable of differentiating into only a limited quantity of specific cell types, these cells are able to overcome the ethical and legal issues accompanying the application of embryonic and fetal stem cells and the mutational effects associated with iPSCs. Moreover, adult stem cells can be used in autogenous form. These cells are present in practically all tissues in the organism. However, adipose tissue seems to be the most advantageous tissue from which to isolate them, because of its abundancy, its subcutaneous location, and the need for less invasive techniques. Adipose tissue-derived stem cells (ASCs) are therefore considered highly promising in present-day regenerative medicine.