RESUMO
Purpose: The ability of MRI-based markers to detect myelin in the brain is limited. This study investigated the potential of combining multiple MRI markers, each targeting distinct myelin properties, to improve myelin characterization. Methods: We acquired ex vivo multiparametric MRI data at 7 Tesla from control and Gli1 -/- mouse brains at postnatal day 10 (P10), which exhibits enhanced myelination in the corpus callosum, followed by myelin basic protein (MBP) stained immunohistochemistry. Results: Although most MRI markers included in this study showed significant differences in the corpus callosum between control and Gli1 -/- , only fractional anisotropy (FA), mean diffusivity (MD), and T 2 had strong correlations with MBP signals. Partial least square regression (PSLR) based on MRI and MBP values from white matter regions suggested that T 2 had the highest contributions to myelin estimation. When both white and gray matter regions were included, inhomogeneous MT ratio and FA showed strong contributions. Conclusion: This study demonstrates the efficacy of multi-parametric MRI in detecting enhanced myelination in the Gli1 -/- mouse brain. T 2 and diffusion MRI parameters showed strong correlation with MBP signals in the genu of the corpus callosum at P10. The contribution of individual MRI parameter for detecting myelin can be evaluated using PLSR.
RESUMO
A major therapeutic goal in demyelinating diseases, such as Multiple Sclerosis, is to improve remyelination, thereby restoring effective axon conduction and preventing neurodegeneration. In the adult central nervous system (CNS), parenchymal oligodendrocyte progenitor cells (pOPCs) and, to a lesser extent, pre-existing oligodendrocytes (OLs) and oligodendrocytes generated from neural stem cells (NSCs) in the sub-ventricular zone (SVZ) are capable of forming new myelin sheaths. Due to their self-renewal capabilities and the ability of their progeny to migrate widely within the CNS, NSCs represent an additional source of remyelinating cells that may be targeted to supplement repair by pOPCs. However, in demyelinating disorders and disease models, the NSC contribution to myelin repair is modest and most evident in regions close to the SVZ. We hypothesized that NSC-derived cells may compete with OPCs to remyelinate the same axons, with pOPCs serving as the primary remyelinating cells due to their widespread distribution within the adult CNS, thereby limiting the contribution of NSC-progeny. Here, we have used a dual reporter, genetic fate mapping strategy, to characterize the contribution of pOPCs and NSC-derived OLs to remyelination after cuprizone-induced demyelination. We confirmed that, while pOPCs are the main remyelinating cells in the corpus callosum, NSC-derived cells are also activated and recruited to demyelinating lesions. Blocking pOPC differentiation genetically, resulted in a significant increase in the recruitment NSC-derived cells into the demyelinated corpus callosum and their differentiation into OLs. These results strongly suggest that pOPCs and NSC-progeny compete to repair white matter lesions. They underscore the potential significance of targeting NSCs to improve repair when the contribution of pOPCs is insufficient to affect full remyelination.
RESUMO
Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.
