Researchers make counterintuitive discoveries about immune-like characteristics of cells

Date:
October 16, 2020
Source:
Vanderbilt University
Summary:
Biologists reveal that tissue perturbations by chemotherapy agents
promote stem cell expansion and that fibroblast cells exhibit
unexpected, immune-like behavior.



FULL STORY ========================================================================== Vanderbilt University researchers have reported the counterintuitive
discovery that certain chemotherapeutic agents used to treat tumors can
have the opposite effect of tissue overgrowth in normal, intact mammary
glands, epidermis and hair follicles. The researchers also are the
first to report the discovery of an innate immune signaling pathway in fibroblasts -- the spindle-shaped cells responsible for wound healing and collagen production -- that causes cells to proliferate. Such signaling pathways previously were attributed only to immune cells.


==========================================================================
The article describing the research, "DNA Damage Promotes Epithelial Hyperplasia and Fate Mis-specification via Fibroblast Inflammasome
Activation," was published in the journal Developmental Cell on Oct. 13.

The findings of this work, led by postdoctoral fellow Lindsey Seldin and Professor and Chair of the Department of Cell and Developmental Biology
Ian Macara, have broad implications for diseases associated with the
immune system like psoriasis, as well as cancer and stem cell research.

Understanding the functionality of stem cells and the way that their
behavior is regulated has been a longstanding research interest for
Seldin. "Normal stem cells have an amazing ability to continuously
divide to maintain tissue function without forming tumors," she
explained. "We wanted to understand what happens to these cells in
their native environment when subjected to damage, and if the response
was connected to a specific tissue." By testing perturbations to the epidermis, mammary gland and hair follicles vis-a`-vis mechanical damage
or DNA damage through chemotherapeutic agents, the researchers saw a paradoxical response: Stem cells, which otherwise would divide slowly,
instead divided rapidly, promoting tissue overgrowth.

When the tissues were subjected to DNA damage, their stem cells
overly proliferated, giving rise to different cells than they normally
would. "This was a very perplexing result," said Seldin, the paper's
lead author. "We were determined to figure out if this was a direct
response by the stem cells themselves or by inductive signals within
their environment." The key clue was that stem cells isolated from the
body did not behave the same way as in intact tissue -- an indication
that the response must be provoked from signals being sent to the stem
cells from other surrounding cell types.

The investigators turned their attention to fibroblasts, the predominant component of the tissue microenvironment. When fibroblasts in the
epidermis were removed, the stem cell responsiveness to DNA damage was diminished, indicating that they played an important role. RNA sequencing revealed that fibroblasts can signal by way of inflammasomes -- complexes within cells that help tissues respond to stress by clearing damaged cells
or pathogens, which also in this case caused stem cells to divide. "This
is an astounding discovery," said Macara. "Inflammasome signaling
has previously been attributed only to immune cells, but now it seems
that fibroblasts can assume an immune- like nature." Seldin intends to replicate this work in the mammary gland to determine whether fibroblasts initiate the same innate immune response as in the epidermis, and more
broadly how fibroblasts contribute to the development of cancer and
other diseases associated with the immune system.

This work was supported by NCI/NIH grants R35CA132898, F32CA213794 and T32CA119925, as well as American Cancer Society grant PF-18-007-01-CCG.


========================================================================== Story Source: Materials provided by Vanderbilt_University. Original
written by Marissa Shapiro. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Lindsey Seldin, Ian G. Macara. DNA Damage Promotes Epithelial
Hyperplasia
and Fate Mis-specification via Fibroblast Inflammasome Activation.

Developmental Cell, 2020; DOI: 10.1016/j.devcel.2020.09.021 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201016090220.htm

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