Stem Cell Niche Dynamics: From Homeostasis to Carcinogenesis

The stem cell microenvironment is involved in regulating the fate of the stem cell with respect to self-renewal, quiescence, and differentiation. Mathematical models are helpful in understanding how key pathways regulate the dynamics of stem cell maintenance and homeostasis. This tight regulation and maintenance of stem cell number is thought to break down during carcinogenesis. As a result, the stem cell niche has become a novel target of cancer therapeutics. Developing a quantitative understanding of the regulatory pathways that guide stem cell behavior will be vital to understanding how these systems change under conditions of stress, inflammation, and cancer initiation. Predictions from mathematical modeling can be used as a clinical tool to guide therapy design. We present a survey of mathematical models used to study stem cell population dynamics and stem cell niche regulation, both in the hematopoietic system and other tissues. Highlighting the quantitative aspects of stem cell biology, we describe compelling questions that can be addressed with modeling. Finally, we discuss experimental systems, most notably Drosophila, that can best be used to validate mathematical predictions

Interaction between differentiating cell- and niche-derived signals in hematopoietic progenitor maintenance

Maintenance of a hematopoietic progenitor population requires extensive interaction with cells within a microenvironment or niche. In the Drosophila hematopoietic organ, niche-derived Hedgehog signaling maintains the progenitor population. Here, we show that the hematopoietic progenitors also require a signal mediated by Adenosine deaminase growth factor A (Adgf-A) arising from differentiating cells that regulates extracellular levels of adenosine. The adenosine signal opposes the effects of Hedgehog signaling within the hematopoietic progenitor cells and the magnitude of the adenosine signal is kept in check by the level of Adgf-A secreted from differentiating cells. Our findings reveal signals arising from differentiating cells that are required for maintaining progenitor cell quiescence and that function with the niche-derived signal in maintaining the progenitor state. Similar homeostatic mechanisms are likely to be utilized in other systems that maintain relatively large numbers of progenitors that are not all in direct contact with the cells of the niche

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study

Objective: PTEN, a known tumor suppressor gene, is a mediator of neurodeve- lopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. Methods: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6–12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelop- mental evaluations and structured dysmorphology examinations were con- ducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. Results: One hundred and seven patients with PHTS (median age 8.7 years; range 3–21 years) and 38 controls were enrolled. ASD and epi- lepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. Interpretation: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS

Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated

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Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the ‘equilibrium signal’ in order to distinguish it from the ‘niche signal’. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A) (Mondal et al., 2011). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr. DOI: http://dx.doi.org/10.7554/eLife.03626.00

Nomenclature and definition in asymmetric regional body overgrowth

We designate a novel term “isolated lateralized overgrowth” (ILO) for the findings previously described as “isolated hemihypertrophy” and “isolated hemihyperplasia.” ILO is defined as lateralized overgrowth in the absence of a recognized pattern of malformations, dysplasia, or morphologic variants. ILO is likely genetically heterogeneous. Further study is required to determine more of the underlying genetic etiologies and potential associations with currently unrecognized patterns of malformation.National Cancer Institute, Grant number: K08CA193915; Alex’s Lemonade Stand Foundationfor Childhood Cancer; St. Baldrick’s Foundatio

Concepciones de escritura de estudiantes de tres especialidades del Máster de Formación de Profesorado de Secundaria y propuesta de un taller de escritura académica y profesional

El proyecto explorará las concepciones predominantes sobre enseñanza y aprendizaje de la escritura en alumnos de distintas especialidades (Lengua Castellana y Literatura, Ciencias Naturales y Ciencias Sociales) del Máster de Formación del Profesorado