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cells, e.g., liver stellate cells, which could also migrate to the tissue
from outside of the organ or proliferate upon injury in the tissue/
organ itself. (5) Immune cells, e.g., macrophages, which could
migrate to the injured organ from the bone marrow through the
blood. It is also important to know that there is evidence that
trans-differentiation is a phenomenon, which is possibly participat-
ing upon regeneration, and could also contribute to the restoration
of tissue function and structure. But again, the importance of trans-
differentiation in regeneration is currently under investigation.
Kinetics, function and significance of the different cells in tissue
regeneration are also under intense investigation. During the last
decade, studies have unveiled the presence, characterizations and
importance of tissue progenitors. The role of these “adult tissue-
specific” stem cells is now beginning to be unraveled. In particular,
the role of these tissue-specific progenitors in tissue injury and
regeneration is beginning to be investigated and debated. The
complexity of the regenerative process is not only due to the need
to understand the response to injury of the tissue parenchymal
cells. Also the interaction, cross talk and dependence of regenera-
tion on the non-parenchymal cells like endothelial cells, tissue
macrophages, and the injured cells themselves needs to be
addressed. The regenerative process is dependent on a network of
extracellular, cell membrane components and intracellular path-
ways. The molecular mediators of regeneration include small mol-
ecules, e.g., serotonin delivered by circulating platelets, secreted
factors as chemokines and cytokines, cellular membrane factors as
receptors and cell-bound ligands, e.g., TNF
and intracellular net-
works of signaling molecules and scaffold proteins. This complex
molecular and cellular environment needs to be coordinated upon
injury to navigate the regeneration process and also terminate it
upon completion. The significant role of IL-6 in tissue regenera-
tion was reported almost two decades ago (
63
). The initial study
from the group of Rebecca Taub, who knew about the initial early
activation of STAT3 and NF
α
B as reported by others upon liver
resection, has shown that IL-6 is upstream to STAT3 activation
and is essential for liver regeneration following hepatectomy. Today,
IL-6 signaling and trans-signaling effects are apparent in tissue
regeneration. Below, we will discuss the current understanding of
the contribution of the IL-6-gp130 pathways to tissue regenera-
tion in different organs.
Our groups have reported that the IL-6 signaling and trans-
signaling and the gp130 membrane protein are essential for tissue
regeneration in various organs including hematopoietic stem cells
(
9
); liver (
26, 64, 65
); kidney (
66
) and salivary function preserva-
tion (unpublished results). The reason for the broad tissue regen-
eration effect has been recently unfolded. IL-6 produced by
monocytes and macrophages following tissue injury, anchors to
IL-6R, which is expressed mostly on leukocytes and hepatocytes.
κ
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