Biomedical subjects

Lisa M Hoffman

Publications and source records attributed to Lisa M Hoffman.

6 recordsLinked to original sources

PubMed2006

BMP action in skeletogenesis involves attenuation of retinoid signaling.

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.

Aldehyde Dehydrogenase↗

PubMed2005

X-inactivation status varies in human embryonic stem cell lines.

Human embryonic stem cells (hESCs) derived from human blastocysts have an apparently unlimited proliferative capacity and can differentiate into ectoderm, mesoderm, and endoderm. As such, hESC lines have enormous potential for use in cell replacement therapies. It must first be demonstrated, however, that hESCs maintain a stable karyotype and phenotype and that gene expression is appropriately regulated. To date, different hESC lines exhibit similar patterns of expression of markers associated with pluripotent cells. However, the evaluation of epigenetic status of hESC lines has only recently been initiated. One example of epigenetic gene regulation is dosage compensation of the X chromosome in mammalian females. This is achieved through an epigenetic event referred to as X-chromosome inactivation (XCI), an event initiated upon cellular differentiation. We provide the first evidence that undifferentiated hESC lines exhibit different patterns of XCI.

Aneuploidy↗

PubMed2005

Characterization and culture of human embryonic stem cells.

Human embryonic stem cells have been defined as self-renewing cells that can give rise to many types of cells of the body. How and whether these cells can be manipulated to replace cells in diseased tissues, used to screen drugs and toxins, or studied to better understand normal development, however, depends on knowing more about their fundamental properties. Many different human embryonic stem cell lines--which are pluripotent, proliferate indefinitely in vitro and maintain a normal, euploid karyotype over extended culture--have now been derived, but whether these cell lines are in fact equivalent remains unclear. It will therefore be important to define robust criteria for the assessment of both existing and newly derived cell lines and for the validation of new culture conditions.

Biomarkers↗

PubMed2005

Human embryonic stem cell stability.

Human embryonic stem cells (hESCs) are derived from human preimplantation embryos, and exhibit the defining characteristics of immortality and pluripotency. Indeed, these cell populations can be maintained for several years in continuous culture, and undergo hundreds of population doublings. hESCs are thus likely candidates for source of cells for cell replacement therapies. Although hESC lines appear stable in their expression of cytokine markers, expression of telomerase, ability to differentiate, and maintenance of a stable karyotype, several other aspects of stability have not yet been addressed, including mitochondrial sequencing, methylation patterns, and fine resolution cytogenetic analysis. Because of the potential utility of hESCs, it will be of utmost importance to evaluate the stability of these aspects of ESC biology.

Animals↗

PubMed2003

Revisiting the role of retinoid signaling in skeletal development.

Several years ago, it was discovered that an imbalance of vitamin A during embryonic development has dramatic teratogenic effects. These effects have since been attributed to vitamin A's most active metabolite, retinoic acid (RA), which itself profoundly influences the development of multiple organs including the skeleton. After decades of study, researchers are still uncovering the molecular basis whereby retinoids regulate skeletal development. Retinoid signaling involves several components, from the enzymes that control the synthesis and degradation of RA, to the cytoplasmic RA-binding proteins, and the nuclear receptors that modulate gene transcription. As new functions for each component continue to be discovered, their developmental roles appear increasingly complex. Interestingly, each component has been implicated in skeletal development. Moreover, retinoid signaling comes into play at distinct stages throughout the developmental sequence of skeletogenesis, highlighting a fundamental role for this pathway in forming the adult skeleton. Consistent with these roles, manipulation of the retinoid signaling pathway significantly affects the expression of the skeletogenic master regulatory factors, Sox9 and Cbfa1. In addition to the fact that we now have a greater understanding of the retinoid signaling pathway on a molecular level, much more information is now available to begin placing retinoid signaling within the context of other factors that regulate skeletogenesis. Here we review these recent advances and describe our current understanding of how retinoid signaling functions to coordinate skeletal development. We also discuss future directions and clinical implications in this field.

Animals↗

PubMed2003

Molecular mechanisms regulating chondroblast differentiation.

BACKGROUND: Formation of the cartilage template involves a multi-step process in which prechondrogenic mesenchymal cells form condensations prior to differentiating into matrix-producing chondroblasts. Retinoids, particularly retinoic acid, are among the numerous signaling molecules that have been implicated in this process. A proper balance of retinoids is essential for normal skeletal development in that too much or too little negatively impacts skeletogenesis. During the past few years, substantial advances have been made in our understanding of the role of retinoid signaling in these processes, which is reviewed in this report. METHODS: To examine the function of retinoid signaling in skeletal development, transgenic mice that overexpressed a weak, constitutively active retinoic acid receptor (retinoic acid receptor-alpha) in their developing limbs were generated. The mice presented with a range of skeletal abnormalities. To examine the mechanisms responsible for these abnormalities, primary limb mesenchymal cultures from the transgenic mice were compared with cultures from wild-type mice. In addition, to address the molecular basis of retinoic acid receptor action, retinoic acid receptor activity in the primary cultures was manipulated with use of retinoic acid receptor-selective agonists and antagonists. The evaluation of the response to the manipulation of retinoic acid receptors was followed by histological studies and by the use of Northern blot analysis and reporter assays to analyze changes in the expression of chondrocytic markers and to monitor transcription factor activity, respectively. RESULTS: The evidence reviewed here indicates that retinoids maintain cells within condensations in a prechondrogenic, mesenchymal cell state, which prevents the cells from differentiating into chondroblasts. More recent studies have demonstrated that the inhibition of receptor-mediated retinoid signaling induces the expression of Sox9, a transcription factor that is considered a "master switch" for the differentiation of chondroblasts. These effects are largely mediated by the activation of the p38 MAPK signaling cascade. CONCLUSIONS: These findings demonstrate that retinoid receptor-mediated repression is both necessary and sufficient for chondroblast differentiation. Moreover, retinoic acid receptor repression acts downstream of BMP signaling or in a distinct pathway to activate p38 MAPK, which in turn induces chondroblast differentiation.

Animals↗