Stem cells are differentially regulated during development, regeneration and homeostasis in flatworms

The flatworm stem cell system is exceptional within the animal kingdom, as totipotent stem cells (neoblasts) are the only dividing cells within the organism. In contrast to most organisms, piwi-like gene expression in flatworms is extended from germ cells to somatic stem cells. We describe the isolation and characterization of the piwi homologue macpiwi in the flatworm Macrostomum lignano. We use in situ hybridization, antibody staining and RNA interference to study macpiwi expression and function in adults, during postembryonic development, regeneration and upon starvation. We found novelties regarding piwi function and observed differences to current piwi functions in flatworms. First, macpiwi was essential for the maintenance of somatic stem cells in adult animals. A knock-down of macpiwi led to a complete elimination of stem cells and death of the animals. Second, the regulation of stem cells was different in adults and regenerates compared to postembryonic development. Third, sexual reproduction of M. lignano allowed to follow germline formation during postembryonic development, regeneration, and starvation. Fourth, piwi expression in hatchlings further supports an embryonic formation of the germline in M. lignano. Our findings address new questions in flatworm stem cell research and provide a basis for comparison with higher organisms.     

Stem cells and skin regeneration

Stem cells represent a great hope for regenerative medicine. In adult life, stem cell deposits are kept in organ niches; the need for tissue or organ regeneration mobilizes stem cells via the SDF-1-CXCR4 regulation axis. Constant regeneration of the skin is achieved due to stem cell differentiation within the epidermis and the hair follicle; thus, skin may serve as an excellent source of stem cells. This is of paramount importance in the treatment of chronic skin wounds and burns.     

Stem cells in liver regeneration and therapy

The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by the rapid division of mature cells. Proliferation of the parenchymal cells, i.e. hepatocytes and epithelial cells of the bile duct, is regulated by numerous cytokine/growth-factor-mediated pathways and is synchronised with extracellular matrix degradation and restoration of the vasculature. Resident hepatic stem/progenitor cells have also been identified in small numbers in normal liver and implicated in liver tissue repair. Their putative role in the physiology, pathophysiology and therapy of the liver, however, is not yet precisely known. Hepatic stem/progenitor cells also known as “oval cells” in rodents have been implicated in liver tissue repair, at a time when the capacity for hepatocyte and bile duct replication is exhausted or experimentally inhibited (facultative stem/progenitor cell pool). Although much more has to be learned about the role of stem/progenitor cells in the physiology and pathophysiology of the liver, experimental analysis of the therapeutic value of these cells has been initiated. Transplantation of hepatic stem/progenitor cells or in vivo pharmacological activation of the pool of hepatic stem cells may provide novel modalities for the therapy of liver diseases. In addition, extrahepatic stem cells (e.g. bone marrow cells) are being investigated for their contribution to liver regeneration. Hepatic progenitor cells derived from embryonic stem cells are included in this review, which also discusses future perspectives of stem cell-based therapies for liver diseases.     

Stem cells in the face: tooth regeneration and beyond

The face distinguishes one person from another. Postnatal orofacial tissues harbor rare cells that exhibit stem cell properties. Despite unmet clinical needs for reconstruction of tissues lost in congenital anomalies, infections, trauma, or tumor resection, how orofacial stem/progenitor cells contribute to tissue development, pathogenesis, and regeneration is largely obscure. This perspective article critically analyzes the current status of our understanding of orofacial stem/progenitor cells, identifies gaps in our knowledge, and highlights pathways for the development of regenerative therapies.     

Stem and progenitor cells in liver regeneration and repair

Mammalian liver has a unique capacity to regenerate following resection or injury, and recovery of liver mass is mainly through proliferation of remaining adult hepatocytes. However, in pathologic conditions, especially during acute liver failure (ALF) and advanced stages of chronic liver disease (CLD), regeneration eventually fails and orthothopic liver transplantation (OLT) represents the only curative approach. The clinical scenario of a world-wide increasing incidence of end-stage CLD and an associated lack of organ availability has led several laboratories to explore the feasibility and efficiency of experimental alternatives to OLT involving cellular therapy. This review presents experimental and clinical studies performed in the last 10-15 years where adult and embryonic hepatocytes, hepatic stem/progenitor cells and extrahepatic stem cells have been used as transplantable cell sources.     

Stem cells and pulmonary metamorphosis: new concepts in repair and regeneration

Adult stem cells are likely to have much more versatile differentiation capabilities than once believed. Numerous studies have appeared over the past decade demonstrating the ability of adult stem cells to differentiate into a variety of cells from non-hematopoietic organs, including the lung. The goal of this review is to provide an overview of the growth factors which are thought to be involved in lung development and disease, describe the cells within the lung that are believed to replace cells that have been injured, review the studies that have demonstrated the transformation of bone marrow-derived stem cells into lung cells, and describe potential clinical applications with respect to human pulmonary disease.     

Stem cells sources for intervertebral disc regeneration

Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments.Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers(e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration.     

Stem/progenitor cells in liver injury repair and regeneration

Morbidity and mortality from cirrhosis is increasing rapidly in the world. Currently, orthotopic liver transplantation is the only definitive therapeutic option. However, its clinical use is limited, because of poor long‐term graft survival, donor organ shortage and high costs associated with the procedure. Stem cell replacement strategies are therefore being investigated as an attractive alternative approach to liver repair and regeneration. In this review we discuss recent preclinical and clinical investigations that explore the therapeutic potential of stem cells in repair of liver injuries. Several types of stem cells. including embryonic stem cells, haematopoietic stem cells and mesenchymal stem cells, can be induced to differentiate into hepatocyte‐like cells by defined culture conditions in vitro. Stem cell transplantation has been shown to significantly improve liver function and increase animal survival in experimentally‐induced liver‐injury models. Moreover, several pilot clinical studies have reported encouraging therapeutic effects in patients treated with stem cells. Although there remain many unresolved issues, the available data support the notion that stem cell technology may lead to the development of effective clinical modalities for human liver diseases.     

Salivary gland stem cells: A review of development,regeneration and cancer

Salivary glands are responsible for maintaining the health of the oral cavity and are routinely damaged by therapeutic radiation for head and neck cancer as well as by autoimmune diseases such as Sjögren's syndrome. Regenerative approaches based on the reactivation of endogenous stem cells or the transplant of exogenous stem cells hold substantial promise in restoring the structure and function of these organs to improve patient quality of life. However, these approaches have been hampered by a lack of knowledge on the identity of salivary stem cell populations and their regulators. In this review we discuss our current knowledge on salivary stem cells and their regulators during organ development, homeostasis and regeneration. As increasing evidence in other systems suggests that progenitor cells may be a source of cancer, we also review whether these same salivary stem cells may also be cancer initiating cells.     

Stem cells and early lineage development

The recent derivation of pluripotent stem cell lines from a number of different sources, including reprogrammed adult somatic cells, raises the issue of the developmental equivalence of these different pluripotent states. At least two different states representing the epiblast progenitors in the blastocyst and the pluripotent progenitors of the later gastrulating embryo have been recognized. Understanding the initial developmental status of the different pluripotent lines is critical for defining starting conditions for differentiation toward therapeutically relevant cell types.     

Stem cells are units of natural selection in a colonial ascidian

Stem cells are highly conserved biological units of development and regeneration. Here we formally demonstrate that stem cell lineages are also legitimate units of natural selection. In a colonial ascidian, Botryllus schlosseri, vascular fusion between genetically distinct individuals results in cellular parasitism of somatic tissues, gametes, or both. We show that genetic hierarchies of somatic and gametic parasitism following fusion can be replicated by transplanting cells between colonies. We prospectively isolate a population of multipotent, self-renewing stem cells that retain their competitive phenotype upon transplantation. Their single-cell contribution to either somatic or germline fates, but not to both, is consistent with separate lineages of somatic and germline stem cells or pluripotent stem cells that differentiate according to the niche in which they land. Since fusion is restricted to individuals that share a fusion/histocompatibility allele, these data suggest that histocompatibility genes in Botryllus evolved to protect the body from parasitic stem cells usurping asexual or sexual inheritance.     

Stem cells in normal breast development and breast cancer

Abstract.  The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self-renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem-cell model.