Extracellular matrix regulation in the muscle satellite cell niche

Abstract

Increasing evidence points to extracellular matrix (ECM) components playing integral roles in regulating the muscle satellite cell (SC) niche. Even small alterations to the niche ECM can have profound effects on SC localization, activation, self-renewal, proliferation and differentiation. This review will focus on the ECM components that comprise the niche, how they are modulated in health and disease and how these changes are thought to affect SC function. Particular emphasis will be placed on the pathological niche and interventions that aim to restore healthy structure and function, as a better understanding of the interplay between the SC and its environment will drive more targeted and effective therapies.     

IGF-1, inflammation and stem cells: interactions during muscle regeneration

Insulin-like growth factor-I (IGF-1) is an important mediator in numerous developmental processes, such as proliferation, differentiation, survival, growth, apoptosis and regeneration. Mouse genetics have provided important insights into the signalling mechanisms that are necessary for the coordination of muscle repair. Recent studies on the role of IGF-1 in the promotion of cell recruitment to the injured muscle and the subsequent resolution of the inflammatory response have unveiled new perspectives into local repair mechanisms.     

Myogenic stem cells: regeneration and cell therapy in human skeletal muscle

Human skeletal muscle has been considered as an ideal target for cell-mediated therapy. However, the positive results obtained in dystrophic animal models using the resident precursor satellite cell population have been followed by discouraging evidences obtained in the clinical trials involving Duchenne muscular dystrophy patients. This text reviews the recent advances that many groups have achieved to identify from the stem cell compartment putative candidates for cell therapy. We focused our attention on stem cells with myogenic potential which might be able to improve transplantation efficiency and therefore could be used as a therapeutic tool for neuromuscular diseases.     

Paraxial mesodermal progenitors derived from mouse embryonic stem cells contribute to muscle regeneration via differentiation into muscle satellite cells

Pluripotent embryonic stem (ES) cells hold great potential for cell-based therapies. Although several recent studies have reported the potential of ES cell-derived progenitors for skeletal muscle regeneration, how the cells contribute to reconstitution of the damaged myofibers has remained elusive. Here, we demonstrated the process of injured muscle regeneration by the engraftment of ES cell-derived mesodermal progenitors. Mesodermal progenitor cells were induced by a conventional differentiation system and isolated by flow cytometer of platelet-derived growth factor receptor-alpha (PDGFR-alpha), a marker of paraxial mesoderm, and vascular endothelial growth factor receptor-2 (VEGFR-2), a marker of lateral mesoderm. The PDGFR-alpha(+) population that represented the paraxial mesodermal character demonstrated significant engraftment when transplanted into the injured muscle of immunodeficient mouse. Moreover, the PDGFR-alpha(+) population could differentiate into the muscle satellite cells that were the stem cells of adult muscle and characterized by the expression of Pax7 and CD34. These ES cell-derived satellite cells could form functional mature myofibers in vitro and generate myofibers fused with the damaged host myofibers in vivo. On the other hand, the PDGFR-alpha(-)VEGFR-2(+) population that showed lateral mesodermal character exhibited restricted potential to differentiate into the satellite cells in injured muscle. Our results show the potential of ES cell-derived paraxial mesodermal progenitor cells to generate functional muscle stem cells in vivo without inducing or suppressing gene manipulation. This knowledge could be used to form the foundation of the development of stem cell therapies to repair diseased and damaged muscles.     

The gastrointestinal tract stem cell niche

The gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The intestinal crypt is mainly a proliferative compartment, is monoclonal and is maintained by stem cells. The villus represents the differentiated compartment, and is polyclonal as it receives cells from multiple crypts. In the small intestine, cell migration begins near the base of the crypt, and cells migrate from here emerging onto the villi. The basal crypt cells at position 5 are candidate stem cells. As the function of stem cells is to maintain the integrity of the intestinal epithelium, it must self-renew, proliferate, and differentiate within a protective niche. This niche is made up of proliferating and differentiating epithelial cells and surrounding mesenchymal cells. These mesenchymal cells promote the epithelial-mesenchymal crosstalk required to maintain the niche. A stochastic model of cell division has been proposed to explain how a single common ancestral stem cell exists from which all stem cells in a niche are descended. Our group has argued that these crypts then clonally expand by crypt fission, forming two daughters’ crypts, and that this is the mechanism by which mutated stem cells or even cancer stem cell clones expand in the colon and in the entire gastrointestinal tract. Until recently, the differentiation potential of stem cells into adult tissues has been thought to be limited to cell lineages in the organ from which they were derived. Bone marrow cells are rare among adult stem cells regarding their abundance and role in the continuous, lifelong, physiological replenishment of circulating cells. In human and mice experiments, we have shown that bone marrow can contribute to the regeneration of intestinal myofibroblasts and thereby after epithelium following damage, through replacing the cells, which maintain the stem cells niche. Little is known about the markers characterizing the stem and transit amplifying populations of the gastrointestinal tract, although musashi-1 and hairy and enhancer of split homolog-1 have been proposed. As the mammalian gastrointestinal tract develops from the embryonic gut, it is made up of an endodermally-derived epithelium surrounded by cells of mesoderm origin. Cell signaling between these two tissue layers plays a critical role in coordinating patterning and organogenesis of the gut and its derivatives. Many lines of evidence have revealed that Wnt signaling is the most dominant force in controlling cell proliferation, differentiation, and apoptosis along the crypt-villus axis. We have found Wnt messenger RNAs expression in intestinal subepithelial myofibroblasts and frizzled messenger RNAs expression in both myofibroblasts and crypt epithelium. Moreover, there are many other factors, for example, bone morphogenetic protein, homeobox, forkhead, hedgehog, homeodomain, and platelet-derived growth factor that are also important to stem cell signaling in the gastrointestinal tract.     

Deconstructing human embryonic stem cell cultures: niche regulation of self-renewal and pluripotency

The factors and signaling pathways controlling pluripotent human cell properties, both embryonic and induced, have not been fully investigated. Failure to account for functional heterogeneity within human embryonic stem cell (hESC) cultures has led to inconclusive results in previous work examining extrinsic influences governing hESC fate (self renewal vs. differentiation vs. death). Here, we attempt to reconcile these inconsistencies with recent reports demonstrating that an autologously produced in vitro niche regulates hESCs. Moreover, we focus on the reciprocal paracrine signals within the in vitro hESC niche allowing for the maintenance and/or expansion of the hESC colony-initiating cell (CIC). Based on this, it is clear that separation of hESC-CICs, apart from their differentiated derivatives, will be essential in future studies involving their molecular regulation. Understanding how extrinsic factors control hESC self-renewal and differentiation will allow us to culture and differentiate these pluripotent cells with higher efficiency. This knowledge will be essential for clinical applications using human pluripotent cells in regenerative medicine.     

Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches

Skeletal muscle includes satellite cells, which reside beneath the muscle fiber basal lamina and mainly represent committed myogenic precursor cells, and multipotent stem cells of unknown origin that are present in muscle connective tissue, express the stem cell markers Sca-1 and CD34, and can differentiate into different cell types. We tracked bone marrow (BM)-derived stem cells in both muscle connective tissue and satellite cell niches of irradiated mice transplanted with green fluorescent protein (GFP)-expressing BM cells. An increasing number of GFP+ mononucleated cells, located both inside and outside of the muscle fiber basal lamina, were observed 1, 3, and 6 months after transplantation. Sublaminal cells expressed unambiguous satellite cell markers (M-cadherin, Pax7, NCAM) and fused into scattered GFP+ muscle fibers. In muscle connective tissue there were GFP+ cells located close to blood vessels that expressed the ScaI or CD34 stem-cell antigens. The rate of settlement of extra- and intralaminal compartments by BM-derived cells was compatible with the view that extralaminal cells constitute a reservoir of satellite cells. We conclude that both muscle satellite cells and stem cell marker-expressing cells located in muscle connective tissue can derive from BM in adulthood.     

Identification and regulation of a stage-specific stem cell niche enriched by Nanog-positive spermatogonial stem cells in the mouse testis

The ability of spermatogonial stem cells to acquire embryonic stem cell (ESC) properties in vitro has recently been of great interest. However, studies focused on the in vivo regulation of testicular stem cells have been hampered because the exact anatomical location of these cells is unknown. Moreover, no specialized stem cell niche substructure has been identified in the mammalian testis thus far. It has also been unclear whether the adult mammalian testis houses pluripotent stem cells or whether pluripotency can be induced only in vitro. Here, we demonstrate, for the first time, the existence of a Nanog-positive spermatogonial stem cell subpopulation located in stage XII of the mouse seminiferous epithelial cycle. The efficiency of the cells from seminiferous tubules with respect to prolonged pluripotent gene expression was correlated directly with stage-specific expression levels of Nanog and Oct4, demonstrating the previously unknown stage-specific regulation of undifferentiated spermatogonia (SPG). Testicular Nanog expression marked a radioresistant spermatogonial subpopulation, supporting its stem cell nature. Furthermore, we demonstrated that p21 acts as an upstream regulator of Nanog in SPG and mouse ESCs, and our results demonstrate that promyelocytic leukemia zinc finger is a specific marker of progenitor SPG. Additionally, we describe a novel method to cultivate Nanog-positive SPG in vitro. This study demonstrates the existence and location of a previously unknown stage-specific spermatogonial stem cell niche and reports the regulation of radioresistant spermatogonial stem cells.     

Primer and interviews: The dynamic stem cell niche

A stem cell niche is a microenvironment that supports self‐renewal of a population of stem cells, and their production of differentiated cells. While the definition evokes images of a stem cell Shangri‐La—where a serene stem cell pool nestles within a niche that shelters and sustains it—the reality is much more tumultuous. Niches are subject to an ever‐changing maelstrom of environmental factors, the ravages of old age, and the sly tactics of disease. Presented here is a basic overview of the different ways in which stem cell niches respond to local and systemic environments, and their impact on stem cell behavior. The primer culminates with a discussion of the topic with stem cell and niche biologists D. Leanne Jones, Ph.D., and Tudorita Tumbar, Ph.D. Developmental Dynamics 240:737–743, 2011. © 2011 Wiley‐Liss, Inc.     

Elements of a neural stem cell niche derived from embryonic stem cells

Recent studies show that adult neural tissues can harbor stem cells within unique niches. In the mammalian central nervous system, neural stem cell (NSC) niches have been identified in the dentate gyrus and the subventricular zone (SVZ). Stem cells in the well-characterized SVZ exist in a microenvironment established by surrounding cells and tissue components, including transit-amplifying cells, neuroblasts, ependymal cells, blood vessels, and a basal lamina. Within this microenvironment, stem cell properties, including proliferation and differentiation, are maintained. Current NSC culture techniques often include the addition of molecular components found within the in vivo niche, such as mitogenic growth factors. Some protocols use bio-scaffolds to mimic the physical growth environment of living tissue. We describe a novel NSC culture system, derived from embryonic stem (ES) cells, that displays elements of an NSC niche in the absence of exogenously applied mitogens or complex physical scaffolding. Mouse ES cells were neuralized with retinoic acid and plated on an entactin-collagen-laminin-coated glass surface at high density (250,000 cells/cm(2)). Six to eight days after plating, complex multicellular structures consisting of heterogeneous cell types developed spontaneously. NSC and progenitor cell proliferation and differentiation continued within these structures. The identity of cellular and molecular components within the cultures was documented using RT-PCR, immunocytochemistry, and neurosphere-forming assays. We show that ES cells can be induced to form structures that exhibit key properties of a developing NSC niche. We believe this system can serve as a useful model for studies of neurogenesis and stem cell maintenance in the NSC niche as well as for applications in stem cell transplantation.     

The role of satellite and other functional cell types in muscle repair and regeneration

Journal of Muscle Research and Cell Motility - Skeletal muscles play essential roles in physiological processes, including motor function, energy hemostasis, and respiration. Skeletal muscles also...     

Absence of exogenous satellite cell contribution to regeneration of frozen skeletal muscle

Summary Rat extensor digitorum longus (EDL) muscles were repeatedly frozen and thawed to kill completely all cellular constituents. Within four days, blood vessels and phagocytic cells invaded the muscles. Migrating or circulating myoblasts were not among the invading cells, and could be induced to invade the frozen muscle only when a physical bridge was created with an adjacent intact muscle. A further requirement for migration was that the connective tissue investments of both the frozen EDL and adjacent muscle had to be disrupted. This study demonstrates that regeneration of a muscle is primarily dependent upon the intrinsic satellite cell population, although under some circumstances recruitment of extrinsic cells is possible.     

The realized niche of adult neural stem cells

This review gives an overview of current issues concerning the application of the concept of the stem cell niche to the adult mammalian brain. It describes how the niche manifests itself at different structural levels as well as the main applications that are influenced by this concept. Finally, special regard is given to what is known for the adult human brain and how far the findings from lower animals can be applied in harnessing the regenerative potential of stem cells for therapy.     

Effects of skeletal muscle regeneration on the proliferation potential of satellite cells

Skeletal muscle satellite cells are myogenic stem cells that function to repair damaged muscle fibers. Participation of satellite cells in a regeneration response following muscle injury results in a significant reduction in their cumulative proliferation potential. The magnitude of the reduction is proportional to the number of regeneration responses in which the cells participate.     

Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration

Articular cartilage is difficult to heal once injury or disease occurs. Autologous chondrocyte transplantation is a biological treatment with good prognosis, but donor site morbidity and limited cell source are disadvantages. Currently, mesenchymal stem cells (MSCs) are a promising approach for cartilage regeneration. Despite there being various sources, the best candidate for cartilage regeneration is the one with the greatest chondrogenic potential and the least hypertrophic differentiation. These properties are able to insure that the regenerated tissue is hyaline cartilage of high quality. This review article will summarize relevant literature to justify synovium-derived stem cells (SDSCs) as a tissue-specific stem cell for chondrogenesis by comparing synovium and cartilage with respect to anatomical location and functional structure, comparing the growth characterization and chondrogenic capacity of SDSCs and MSCs, evaluating the application of SDSCs in regenerative medicine and diseases, and discussing potential future directions.     

The case for a metabolic stem cell niche

Despite more than 40 years of experience with the use of haematopoietic stem cells (HSC) in the clinic and the identification of a plethora of regulatory signals of clear relevance to their function, it has proven remarkably difficult to amplify these cells efficiently in culture without a concurrent loss of potential. Based on considerations of haematopoietic environments in the embryo and the adult, on published observations of metabolic compartmentalisation between neighbouring cells in other tissues, and on considerations of the selective pressures acting on the evolution of generative and regenerative systems, we propose that the amplification of HSC may be tied obligatorily to limiting metabolic conditions provided by the niche. We suggest that this conceptually simple arrangement could combine the support of HSC with the containment of self-renewal activity within a rare and highly defined set of physiological sites, whilst avoiding the accumulation of potentially leukaemogenic mutations in the stem cell pool.     

Featured characteristics and pivotal roles of satellite cells in skeletal muscle regeneration

Journal of Muscle Research and Cell Motility - Skeletal muscle, the essential organ for locomotion, as well as energy reservoir and expenditure, has robust regenerative capacity in response to...