Inverse Problem Reveals Conditions for Characteristic Retinal Degeneration Patterns in Retinitis Pigmentosa under the Trophic Factor Hypothesis

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy with a prevalence of about 1 in 4000, affecting approximately 1.5 million people worldwide. Patients with RP experience progressive visual field loss as the retina degenerates, destroying light-sensitive photoreceptor cells (rods and cones), with rods affected earlier and more severely than cones. Spatio-temporal patterns of retinal degeneration in human RP have been well characterised; however, the mechanism(s) giving rise to these patterns have not been conclusively determined. One such mechanism, which has received a wealth of experimental support, is described by the trophic factor hypothesis. This hypothesis suggests that rods produce a trophic factor necessary for cone survival; the loss of rods depletes this factor, leading to cone degeneration. In this paper we formulate a partial differential equation mathematical model of RP in one spatial dimension, spanning the region between the retinal centre (fovea) and the retinal edge (ora serrata). Using this model we derive and solve an inverse problem, revealing for the first time experimentally testable conditions under which the trophic factor mechanism will qualitatively recapitulate the spatio-temporal patterns or retinal regeneration observed in human RP.

Regulation of neuropeptide Y in body microenvironments and its potential application in therapies: a review

Neuropeptide Y (NPY), one of the most abundant neuropeptides in the body, is widely expressed in the central and peripheral nervous systems and acts on the cardiovascular, digestive, endocrine, and nervous systems. NPY affects the nutritional and inflammatory microenvironments through its interaction with immune cells, brain-derived trophic factor (BDNF), and angiogenesis promotion to maintain body homeostasis. Additionally, NPY has great potential for therapeutic applications against various diseases, especially as an adjuvant therapy for stem cells. In this review, we discuss the research progress regarding NPY, as well as the current evidence for the regulation of NPY in each microenvironment, and provide prospects for further research on related diseases.

Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer’s Disease

Objective. Alzheimer’s disease (AD) is associated with cell cycle reentry of mature neurons that subsequently undergo degeneration. This study is aimed to identify key regulators of the cell cycle and their underlying pathways for developing optimal treatment of AD. Methods. RNA sequencing data were profiled to screen for differentially expressed genes in the cell cycle. Correlation of created modules with AD phenotype was computed by weight gene correlation network analysis (WGCNA). Signature genes for trophic factor receptors were determined using Pearson correlation coefficient (PCC) analysis. Results. Among the 13,679 background genes, 775 cell cycle genes and 77 trophic factor receptors were differentially expressed in AD versus nondementia controls. Four coexpression modules were constructed by WGCNA, among which the turquoise module had the strongest correlation with AD. According to PCC analysis, 10 signature trophic receptors most strongly interacting with cell cycle genes were filtered and subsequently displayed in the global regulatory network. Further cross-talking pathways of signature receptors, such as glutamatergic synapse, long-term potentiation, PI3K-Akt, and MAPK signaling pathways, were identified. Conclusions. Our findings highlighted the mechanistic pathways of signature trophic receptors in cell cycle perturbation underlying AD pathogenesis, thereby providing new molecular targets for therapeutic intervention in AD.

Mathematical Models of Retinitis Pigmentosa: The Trophic Factor Hypothesis

Retinitis pigmentosa (RP) is the term used to denote a group of inherited retinal-degenerative conditions that cause progressive sight loss. Individuals with this condition lose their light-sensitive photoreceptor cells, known as rods and cones, over a period of years to decades; degeneration starting in the retinal periphery, and spreading peripherally and centrally over time. RP is a rod-cone dystrophy, meaning that rod health and function are affected earlier and more severely than that of cones. Rods degenerate due to an underlying mutation, whereas the reasons for cone degeneration are unknown. A number of mechanisms have been proposed to explain secondary cone loss and the spatio-temporal patterns of retinal degeneration in RP. One of the most promising is the trophic factor hypothesis, which suggests that rods produce a factor necessary for cone survival, such that, when rods degenerate, cone degeneration follows. In this paper we formulate and analyse mathematical models of RP under the trophic factor hypothesis. These models are constructed as systems of reaction-diffusion partial differential equations in one spatial dimension, and are solved and analysed using a combination of numerical and analytical methods. We predict the conditions under which cones will degenerate following the loss of a patch of rods from the retina, the critical trophic factor treatment rate required to prevent cone degeneration following rod loss and the spatio-temporal patterns of cone loss that would result if the trophic factor mechanism alone were responsible for retinal degeneration.

Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder

The generation of inhibitory interneurons from neural stem cells in the subependymal zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the subependymal zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.

Osteogenic preconditioning in perfusion bioreactors improves vascularization and bone formation by human bone marrow aspirates

Cell-derived extracellular matrix (ECM) provides a niche to promote osteogenic differentiation, cell adhesion, survival, and trophic factor secretion. To determine whether osteogenic preconditioning would improve the bone-forming potential of unfractionated bone marrow aspirate (BMA), we perfused cells on ECM-coated scaffolds to generate naïve and preconditioned constructs, respectively. The composition of cells selected from BMA was distinct on each scaffold. Naïve constructs exhibited robust proangiogenic potential in vitro, while preconditioned scaffolds contained more mesenchymal stem/stromal cells (MSCs) and endothelial cells (ECs) and exhibited an osteogenic phenotype. Upon implantation into an orthotopic calvarial defect, BMA-derived ECs were present in vessels in preconditioned implants, resulting in robust perfusion and greater vessel density over the first 14 days compared to naïve implants. After 10 weeks, human ECs and differentiated MSCs were detected in de novo tissues derived from naïve and preconditioned scaffolds. These results demonstrate that bioreactor-based preconditioning augments the bone-forming potential of BMA.