Wnt/ß-catenin signaling pathway is involved in early dopaminergic differentiation of trabecular meshwork-derived mesenchymal stem cells.

Permanent degeneration and loss of dopaminergic (DA) neurons in substantia nigra is the main cause of Parkinson's disease. Considering the therapeutic application of stem cells in neurodegeneration, we sought to examine the neurogenic differentiation potential of the newly introduced neural crest originated mesenchymal stem cells (MSCs), namely, trabecular meshwork-derived mesenchymal stem cells (TM-MSCs) compared to two other sources of MSCs, adipose tissue-derived stem cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs). The three types of cells were therefore cultured in the presence and absence of a neural induction medium followed by the analysis of their differentiation potentials. Our results showed that TM-MSCs exhibited enhanced neural morphologies as well as higher expressions of MAP2 as the general neuron marker and Nurr-1 as an early DA marker compared to the adipose tissue-derived mesenchymal stem cells (AD-MSCs) and bone marrow-derived stem cells (BMSCs). Also, analysis of Nurr-1 immunostaining showed more intense Nurr-1 stained nuclei in the neurally induced TM-MSCs compared to those in the AD-MSCs, BMSCs, and noninduced control TM-MSCs. To examine if Wnt/beta-catenin pathway drives TM-MSCs towards a DA fate, we treated them with the Wnt agonist (CHIR, 3 µM) and the Wnt antagonist (IWP-2, 3 µM). Our results showed that the expressions of Nurr-1 and MAP2, as well as the Wnt/beta-catenin target genes, c-Myc and Cyclin D1, were significantly increased in the CHIR-treated TM-MSCs, but significantly reduced in those treated with IWP-2. Altogether, we declare first a higher neural potency of TM-MSCs compared to the more commonly used MSCs, BMSCs and ADSCs, and second that Wnt/beta-catenin activation directs the neurally induced TM-MSCs towards a DA fate.

Genetics of sexually dimorphic adipose distribution in humans.

Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.

The Effect of Timing of Mandibular Distraction Osteogenesis on Weight Velocity in Infants Affected by Severe Robin Sequence.

Background: Impaired weight gain is prevalent in Robin Sequence (RS) newborns. Although mandibular distraction osteogenesis (MDO) has been proven to improve oral feeding, its impact on postoperative weight gain remains unclear. The purpose of this study is to explore whether MDO can help RS babies reach a normal weight, as well as the effect of MDO timing on weight velocity. Methods: One hundred infants with severe RS and one hundred with normal controls met the inclusion criteria for the study. Included patients underwent MDO. Weights at different timing points were recorded and analyzed and compared to normal controls. Results: After the distractor removal weights of patients undergoing MDO at <1 month and 1−2 months were close to the normal control (6.81 ± 0.93 kg versus 7.18 ± 0.61 kg, p = 0.012, and 6.82 ± 0.98 kg versus 7.37 ± 0.75 kg, p = 0.033, respectively), the weights of patients undergoing MDO at 2−3 months and 3−4 months still lagged behind (7.56 ± 1.29 kg versus 8.20 ± 0.61 kg, p = 0.000206 and 7.36 ± 1.05 kg versus 8.25 ± 0.77 kg, p = 0.004, respectively). The weights of all RS infants undergoing MDO showed no significant difference compared to the controls when they aged to 1 year (9.34 ± 0.99 kg versus 9.55 ± 0.45 kg, p = 0.254 for MDO at <1 month; 9.12 ± 0.91 kg versus 9.33 ± 0.46 kg, p = 0.100 for MDO at 1 to 2 months; 9.38 ± 0.29 kg versus 9.83 ± 0.53 kg, p = 0.098 for MDO at 2 to 3 months; and 9.38 ± 0.29 kg versus 9.83 ± 0.53 kg, p = 0.098 for MDO at 3 to 4 months). Conclusion: The MDO procedure helped patients with severe RS to reach a normal weight; and MDO intervention was recommended at an early stage for early weight gain.

Key miRNAs in Modulating Aging and Longevity: A Focus on Signaling Pathways and Cellular Targets.

Aging is a multifactorial process accompanied by gradual deterioration of most biological procedures of cells. MicroRNAs (miRNAs) are a class of short non-coding RNAs that post-transcriptionally regulate the expression of mRNAs through sequence-specific binding, contributing to many crucial aspects of cell biology. Several miRNAs are expressed differently in various organisms through aging. The function of miRNAs in modulating aging procedures has been disclosed recently with the detection of miRNAs that modulate longevity in the invertebrate model organisms through the IIS pathway. In these model organisms, several miRNAs have been detected to both negatively and positively regulate lifespan via commonly aging pathways. miRNAs modulate age-related procedures and disorders in different mammalian tissues by measuring their tissue- specific expression in older and younger counterparts, including heart, skin, bone, brain, and muscle tissues. Moreover, several miRNAs have contributed to modulating senescence in different human cells, and the roles of these miRNAs in modulating cellular senescence have allowed illustrating some mechanisms of aging. The review discusses the available data on the role of miRNAs in the aging process, and the roles of miRNAs as aging biomarkers and regulators of longevity in cellular senescence, tissue aging, and organism lifespan have been highlighted.

A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases.

Sirtuin-1 (SIRT1) as a NAD + -dependent Class III protein deacetylase, involves in longevity and various cellular physiological processes. SIRT1 via deacetylating transcription factors regulates cell growth, inflammation, metabolism, hypoxic responses, cell survival, senescence, and aging. MicroRNAs (miRNAs) are short non-coding RNAs that modulate the expression of target genes in a post-transcriptional manner. Recent investigations have exhibited that miRNAs have an important role in regulating cell growth, development, stress responses, tumor formation and suppression, cell death, and aging. In the present review, we summarize recent findings about the roles of miRNAs in regulating SIRT1 and SIRT1-associated signaling cascade and downstream effects, like apoptosis and aging. Here we introduce and discuss how activity and expression of SIRT1 are modulated by miRNAs and further review the therapeutic potential of targeting miRNAs for age-associated diseases that involve SIRT1 dysfunction. Although at its infancy, research on the roles of miRNAs in aging and their function through modulating SIRT1 may provide new insights in deciphering the key molecular pathways related to aging and age-associated disorders.