Developing written information on osteoarthritis for patients: facilitating user involvement by exposure to qualitative research.

INTRODUCTION: In developing a guidebook on osteoarthritis (OA), we collaborated with people who have chronic joint pain (users). But to advise, users need to be aware of and sensitive about their own state of knowledge and educationalists argue that adults sometimes lack such awareness. This paper will report on our experience of providing users with findings from qualitative research to increase awareness of their level of knowledge. METHOD: A summary of the results from qualitative research into people's experiences of living with chronic pain was sent to individual members of two groups of users. It was then used to structure group meetings held to help identify information needed for the guidebook. FINDINGS: Some users found the summary difficult to read and suggested how to simplify it. Nevertheless, it helped most users to become aware of the experiences and views of others who have OA and thus become more sensitive to their own level of knowledge. It also helped them recall experiences that stimulated practical suggestions for managing joint pain in everyday life and provided a way of gently challenging the views of users when they appeared to assume that their views were widely held. The discussions brought to light gaps in the research literature. CONCLUSION: We believe this way of involving users by exposing them to qualitative research findings about lay experiences of living with OA effectively facilitated the users' contributions to the needs of those who have to live with OA, and we believe it has wider applications.

BMP signaling controls formation of a primordial germ cell niche within the early genital ridges.

Stem cells are necessary to maintain tissue homeostasis and the microenvironment (a.k.a. the niche) surrounding these cells controls their ability to self-renew or differentiate. For many stem cell populations it remains unclear precisely what cells and signals comprise a niche. Here we identify a possible PGC niche in the mouse genital ridges. Conditional ablation of Bmpr1a was used to demonstrate that BMP signaling is required for PGC survival and migration as these cells colonize the genital ridges. Reduced BMP signaling within the genital ridges led to increased somatic cell death within the mesonephric mesenchyme. Loss of these supporting cells correlated with decreased levels of the mesonephric marker, Pax2, as well as a reduction in genes expressed in the coelomic epithelium including the putative PGC chemo-attractants Kitl and Sdf1a. We propose that BMP signaling promotes mesonephric cell survival within the genital ridges and that these cells support correct development of the coelomic epithelium, the target of PGC migration. Loss of BMP signaling leads to the loss of the PGC target resulting in reduced PGC numbers and disrupted PGC migration.

Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse.

BACKGROUND: Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors. RESULTS: We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally. CONCLUSION: In the mouse, cholesterol is required for PGC survival and motility. It may act cell-autonomously by regulating clustering of growth factor receptors within PGCs or non cell-autonomously by controlling release of growth factors required for PGC guidance and survival.

BMP signaling regulates PGC numbers and motility in organ culture.

Members of the bone morphogenetic protein (BMP) family play diverse roles in multiple developmental processes. However, in the mouse, mutations in many BMPs, BMP receptors and signaling components result in early embryonic lethality making it difficult to analyze the role of these factors during organogenesis or tissue homeostasis in the adult. To bypass this early lethality, we used an organ culture system to study the role of BMPs during primordial germ cell (PGC) migration. PGCs are the embryonic precursors of the sperm and eggs. BMPs induce formation of primordial germ cells within the proximal epiblast of embryonic day 7.5 (E7.5) mouse embryos. PGCs then migrate via the gut to arrive at the developing gonads by E10.5. Addition of BMP4 or the BMP-antagonist Noggin to transverse slices dissected from E9.5 embryos elevated PGC numbers or reduced PGC numbers, respectively. Noggin treatment also slowed and randomized PGC movements, resulting in a failure of PGCs to colonize the urogenital ridges (UGRs). Based on p-Smad1/5/8 staining, migratory PGCs do not respond to endogenous BMPs. Instead, the somatic cells of the urogenital ridges exhibit elevated p-Smad1/5/8 staining revealing active BMP signaling within the UGRs. Noggin treatment abrogated p-Smad staining within the UGRs and blocked localized expression of Kitl, a cytokine known to regulate the survival and motility of PGCs and Id1, a transcription factor expressed within the UGRs. We propose that BMP signaling regulates PGC migration by controlling gene expression within the somatic cells along the migration route and within the genital ridges.

In vivo germ line stem cell migration: a mouse model.

A stem cell niche is a specialized tissue environment that controls the proliferation and differentiation of its resident stem cells. The functions of these structures have been well characterized in adult organisms. In particular, the bone marrow stem cell niche in mammals has been amenable to analysis because of the ability of transplanted hematopoietic cells to home and to recolonize the bone marrow of an irradiated host. Despite clues from adult models, it remains unclear how stem cells become partitioned into appropriate niches during embryonic development. To examine the earliest steps in niche formation, we created an organ culture system to observe the development of primordial germ cells (PGCs), a migratory stem cell population that will eventually give rise to the gametes. Using this assay, we can watch PGCs as they migrate to colonize the developing gonads and can introduce growth factor agonists or antagonists to test the function of proteins that regulate this process. This provides an unprecedented opportunity to identify the cellular and molecular interactions required for the formation of the germ cell niche.