Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.

Combinatorial transcription codes generate the myriad of cell types during development and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIM-complex mimicking fusion, induces a signature of MN transcriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM domain of Lhx3 are crucial for generating MNs without up-regulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of Isl1 and Lhx3 and the LIM domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog (Shh). RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of using embryonic transcription complexes for producing specific cell types from stem cells. D eveloping central nervous system (CNS) produces a vast number of neuronal types, but adult CNS has only limited capacity to regenerate neurons. This has prompted great interest in identifying methods to produce specific neuronal types from stem cells. Production of differentiated cell types from pluripotent stem cells, such as embryonic stem cells (ESCs), should enable a continuous supply of diseased cell types for drug screening and cell replacement therapy and provide valuable insights into the pathophysiology of human diseases. One important challenge in this effort is to steer stem cells into specific cell types. Recapitulation of normal developmental processes using embryonic inductive signals has been used to drive differentiation of pluripotent stem cells into specific cell types (1). However, this strategy tends to trigger formation of mixed cell types rather than a targeted cell type, because each inductive signal is used in multiple developmental pathways. This shortcoming might be circumvented by using more specific, downstream transcription factors of inductive signals. In this regard, it should be noted that many transcription factors function in combination to determine cell fates during development, suggesting that coexpression of multiple transcription factors could be a more effective method to generate a particular cell type from pluripotent stem cells.Motor neurons (MNs) in the spinal cord project axons to muscles and control their contraction. The developmental pathways to generate MNs have been relatively well studied. In the developing spinal cord, sonic hedgehog (Shh) signal triggers the expression of two LIM homeodomain...

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD. K E Y W O R D Saging, brain vasculature, cerebral blood flow, cognitive decline, functional MRI, mTOR

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