Journal of Cellular Physiology

Teodorczyk, Marcin; Martin‐Villalba, Ana

doi: 10.1002/jcp.21901pmid: 19688773

Glioblastoma multiforme (GBM) is the most common malignant brain tumour in adults. One main source of its high malignancy is the invasion of isolated tumour cells into the surrounding parenchyma, which makes surgical resection an insufficient therapy in nearly all cases. The invasion is triggered by several cell surface receptors including receptor tyrosine kinases (RTKs), G protein‐coupled receptors (GPCRs), TGF‐β receptor, integrins, immunoglobulins, tumour necrosis factor (TNF) family, cytokine receptors, and protein tyrosine phosphatase receptors. The cross‐talk between cell‐surface receptors and the redundancy of downstream effectors make analysis of invasive signals even more complex. Therapies involving inhibition of single receptors do not give promising outcomes and a thorough knowledge of invasive signals of common and exclusive signalling components is required for design of best combinatory treatment schemes to fight the disease. J. Cell. Physiol. 222:1–10, 2010. © 2009 Wiley‐Liss, Inc.

Gering, Martin; Patient, Roger

doi: 10.1002/jcp.21905pmid: 19725072

The Notch signalling pathway is repeatedly employed during embryonic development and adult homeostasis of a variety of tissues. In particular, its frequent involvement in the regulation of stem and progenitor cell maintenance and proliferation, as well as its role in binary fate decisions in cells that are destined to differentiate, is remarkable. Here, we review its role in the development of haematopoietic stem cells during vertebrate embryogenesis and put it into the context of Notch's functions in arterial specification, angiogenic vessel sprouting and vessel maintenance. We further discuss interactions with other signalling cascades, and pinpoint open questions and some of the challenges that lie ahead. J. Cell. Physiol. 222:11–16, 2010. © 2009 Wiley‐Liss, Inc.

Eliasson, Pernilla; Jönsson, Jan‐Ingvar

doi: 10.1002/jcp.21908pmid: 19725055

The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short‐lived progenitors, which in turn arise from a rare population of pluripotent and self‐renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell‐cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self‐renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self‐renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia‐mediated regulation. J. Cell. Physiol. 222:17–22, 2010. © 2009 Wiley‐Liss, Inc.

Richardson, Stephen M.; Hoyland, Judith A.; Mobasheri, Reza; Csaki, Constanze; Shakibaei, Mehdi; Mobasheri, Ali

doi: 10.1002/jcp.21915pmid: 19725073

Defects of load‐bearing connective tissues such as articular cartilage and intervertebral disc (IVD) can result from trauma, degenerative, endocrine, or age‐related disease. Current surgical and pharmacological options for the treatment of arthritic rheumatic conditions in the joints and spine are ineffective. Cell‐based surgical therapies such as autologous chondrocyte transplantation (ACT) have been in clinical use for cartilage repair for over a decade but this approach has shown mixed results. This review focuses on the potential of mesenchymal stem cells (MSCs) as an alternative to cells derived from patient tissues in autologous transplantation and tissue engineering. Here we discuss the prospects of using MSCs in regenerative medicine and summarize the advantages and disadvantages of these cells in articular cartilage and IVD tissue engineering. We discuss the conceptual and practical difficulties associated with differentiating and pre‐conditioning MSCs for subsequent survival in a physiologically harsh extracellular matrix, an environment that will be highly hypoxic, acidic, and nutrient deprived. Implanted MSCs will be exposed to traumatic physical loads and high levels of locally produced inflammatory mediators and catabolic cytokines. We also explore the potential of culture models of MSCs, fully differentiated cells and co‐cultures as “proof of principle” ethically acceptable “3Rs” models for engineering articular cartilage and IVD in vitro for the purpose of replacing the use of animals in arthritis research. J. Cell. Physiol. 222:23–32, 2010. © 2009 Wiley‐Liss, Inc.

Wang, Ping; Hou, Steven X.

doi: 10.1002/jcp.21928pmid: 19739102

The digestive systems in mammals and Drosophila are quite different in terms of their complexity and organization, but their biological functions are similar. The Drosophila midgut is a functional equivalent of the mouse small intestine. Adult intestinal stem cells (ISCs) have been identified in both the mouse small intestine and Drosophila midgut. The anatomy and cell renewal in the Drosophila midgut are similar to those in the mouse small intestine: the intestinal epithelium in both systems is a tube composed of epithelial cells with absorptive and secretory functions; the Notch signaling controls absorptive versus secretory fate decisions in the intestinal epithelium; cell renewal in both systems starts from stem cells in the basal cell layer, and the differentiated cells then move toward the lumen. However, it is clear that the stem cells in the two systems are regulated in different ways. In this review, we will compare cell renewal and stem cell regulation in the two systems. J. Cell. Physiol. 222:33–37, 2010. © 2009 Wiley‐Liss, Inc.

Uong, Audrey; Zon, Leonard I.

doi: 10.1002/jcp.21935pmid: 19795394

Melanocytes are pigment‐producing cells in the skin of humans and other vertebrates. A number of genes involved in melanocyte development and vertebrate pigmentation have been characterized, largely through studies of a diversity of pigment mutations in a variety of species. Embryonic development of the melanocyte initiates with cell fate specification in the neural crest, which is then followed by cell migration and niche localization. Many genes involved in melanocyte development have also been implicated in the development of melanoma, an aggressive and fatal form of skin cancer that originates in the melanocyte. Although early stage melanomas that have not spread to the lymph nodes can be excised with little risk of recurrence, patients diagnosed with metastatic melanoma have a high mortality rate due to the resistance of most tumors to radiotherapy and chemotherapy. Transformed melanocytes that develop into melanomas proliferate abnormally and often begin to grow radially in the skin. Vertical growth can then follow this radial growth, leading to an invasion through the basement membrane into the underlying dermis and subsequent metastasis. It is still unclear, however, how a normal melanocyte becomes a melanoma cell, and how melanoma utilizes the properties of the normal melanocyte and its progenitors in its progression. The goal of this mini‐review is to highlight the role of melanocyte developmental pathways in melanoma, and to discuss recent studies and tools being used to illuminate this connection. J. Cell. Physiol. 222:38–41, 2010. © 2009 Wiley‐Liss, Inc.

Chou, Jonathan; Provot, Sylvain; Werb, Zena

doi: 10.1002/jcp.21943pmid: 19798694

There is increasing evidence that the numerous mechanisms that regulate cell differentiation during normal development are also involved in tumorigenesis. In breast cancer, differentiation markers expressed by the primary tumor are routinely profiled to guide clinical decisions. Indeed, numerous studies have shown that the differentiation profile correlates with the metastatic potential of tumors. The transcription factor GATA3 has emerged recently as a strong predictor of clinical outcome in human luminal breast cancer. In the mammary gland, GATA3 is required for luminal epithelial cell differentiation and commitment, and its expression is progressively lost during luminal breast cancer progression as cancer cells acquire a stem cell‐like phenotype. Importantly, expression of GATA3 in GATA3‐negative, undifferentiated breast carcinoma cells is sufficient to induce tumor differentiation and inhibits tumor dissemination in a mouse model. These findings demonstrate the exquisite ability of a differentiation factor to affect malignant properties, and raise the possibility that GATA3 or its downstream genes could be used in treating luminal breast cancer. This review highlights our recent understanding of GATA3 in both normal mammary development and tumor differentiation. J. Cell. Physiol. 222:42–49, 2010. © 2009 Wiley‐Liss, Inc.

Link, Kevin A.; Chou, Fu‐Sheng; Mulloy, James C.

doi: 10.1002/jcp.21950pmid: 19813271

Hematopoietic development requires coordinated actions from a variety of transcription factors. The core binding factor (CBF), consisting of a Runx protein and the CBFβ protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFβ knockout mice underscore the necessity of this complex for definitive hematopoiesis. Despite the requirement for CBF in establishing definitive hematopoiesis, Runx1 loss has minimal impact on maintaining the HSC state postnatally, while CBFβ may continue to be essential. Lineage commitment, on the other hand, is significantly affected upon CBF loss in the adult, indicating a primary role for this complex in modulating differentiation. Given the impact of normal CBF function in the hematopoietic system, the severe consequences of disrupting CBF activity, either through point mutations or generation of fusion genes, are obvious. The physiologic role of CBF in differentiation is subverted to an active process of self‐renewal maintenance by the genetic aberrations, through several possible mechanisms, contributing to the development of hematopoietic malignancies including myelodysplastic syndrome and leukemia. The major impact of CBF on the hematopoietic system in both development and disease highlights the need for understanding the intricate functions of this complex and reiterate the necessity of continued efforts to identify potential points of therapeutic intervention for CBF‐related diseases. J. Cell. Physiol. 222:50–56, 2010. © 2009 Wiley‐Liss, Inc.

Colvin, Gerald A.; Berz, David; Liu, Liansheng; Dooner, Mark S.; Dooner, Gerri; Pascual, Sheila; Chung, Samuel; Sui, Yunxia; Quesenberry, Peter J.

doi: 10.1002/jcp.21918pmid: 19774557

Purified long‐term multilineage repopulating marrow stem cells have been considered to be homogenous, but functionally these cells are heterogeneous. Many investigators urge clonal studies to define stem cells but, if stem cells are truly heterogeneous, clonal studies can only define heterogeneity. We have determined the colony growth and differentiation of individual lineage negative, rhodamine low, Hoechst low (LRH) stem cells at various times in cytokine culture, corresponding to specific cell cycle stages. These highly purified and cycle synchronized (98% in S phase at 40 h of culture) stem cells were exposed to two cytokine cocktails for 0, 18, 32, or 40 h and clonal differentiation assessed 14 days later. Total heterogeneity as to gross colony morphology and differentiation stage was demonstrated. This heterogeneity showed patterns of differentiation at different cycle times. These data hearken to previous suggestions that stem cells might be similar to radioactive isotopes; decay rate of a population of radioisotopes being highly predictable, while the decay of individual nuclei is heterogeneous and unpredictable (Till et al., 1964). Marrow stem cells may be most adequately defined on a population basis; stem cells existing in a continuum of reversible change rather than a hierarchy. J. Cell. Physiol. 222:57–65, 2010. © 2009 Wiley‐Liss, Inc.

Winkler, G. Sebastiaan

doi: 10.1002/jcp.21919pmid: 19746446

The mammalian BTG/Tob family comprises six proteins (BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2), which regulate cell cycle progression in a variety of cell types. They are characterised by the conserved N‐terminal domain spanning 104–106 amino acids. Recent biochemical and structural data indicate that the conserved BTG domain is a protein–protein interaction module, which is capable of binding to DNA‐binding transcription factors as well as the paralogues CNOT7 (human Caf1/Caf1a) and CNOT8 (human Pop2/Calif/Caf1b), two deadenylase subunits of the Ccr4‐Not complex. Consistent with this finding, several members of the BTG/Tob family are shown to be implicated in transcription in the nucleus and cytoplasmic mRNA deadenylation and turnover. The C‐terminal regions are less conserved and appear to mediate protein–protein interactions that are unique to each family member. The human and mouse BTG/Tob proteins will be the focus of this review and structural aspects of BTG/Tob interactions with components of the Ccr4‐Not complex, and the role of the BTG/Tob proteins in the regulation of gene expression, tumourigenesis and cancer will be discussed. J. Cell. Physiol. 222:66–72, 2010. © 2009 Wiley‐Liss, Inc.