Background
The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive.
Aims & Methods
We employed IL-1α and IL-1β-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis.
Results
Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 folds-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ (p=0.004). IL-1α mRNA levels were 2 folds lower in IL-1β-deficient mice, and IL-1β transcripts were 3 folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells is required for steatohepatitis development.
Conclusions
These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit development of steatohepatitis should be explored.
When assembling a nephron during development a multipotent stem cell pool becomes
restricted as differentiation ensues. A faulty differentiation arrest in this
process leads to transformation and initiation of a Wilms’ tumor.
Mapping these transitions with respective surface markers affords accessibility to
specific cell subpopulations. NCAM1 and CD133 have been previously suggested to mark
human renal progenitor populations. Herein, using cell sorting, RNA sequencing,
in vitro studies with serum-free media and in vivo
xenotransplantation we demonstrate a sequential map that links human kidney
development and tumorigenesis; In nephrogenesis,
NCAM1+CD133− marks
SIX2+ multipotent renal stem cells transiting to
NCAM1+CD133+ differentiating segment-specific
SIX2− epithelial progenitors and
NCAM1−CD133+ differentiated nephron
cells. In tumorigenesis, NCAM1+CD133−
marks SIX2+ blastema that includes the ALDH1+ WT
cancer stem/initiating cells, while NCAM1+CD133+ and
NCAM1−CD133+ specifying early and late
epithelial differentiation, are severely restricted in tumor initiation capacity and
tumor self-renewal. Thus, negative selection for CD133 is required for defining
NCAM1+ nephron stem cells in normal and malignant
nephrogenesis.
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