INSIGHTS | PERSPECTIVES
prising because both cell types are classified as mesodermal lineages. For instance,
it also has been observed that adipose-resident cell lineages could be converted to
skeletal stem cells and skeletal cell lineages
through BMP signaling (6). However, recent
studies point to tremendous functional heterogeneity in fibroblast and adipocyte cell
lineages (7–9). Therefore, it is important to
consider the role that fibroblast diversity
may play alongside interpretations of fibroblast plasticity.
What is the basis of fibroblast heteroge-
neity? Both cell-intrinsic and extrinsic fac-
tors seem to apply. Known determinants of
intrinsic functional diversity in fibroblasts
include their ontogeny in a particular fibro-
blast stem cell-progenitor cell lineage, their
tissue of origin (such as skin, lung, or bone),
their positional identity (dorsal, ventral,
anterior, posterior), and the developmental
stage (fetal, adult, aged) of the organism
(7–9). Additionally, differences due to vari-
ations in extrinsic signaling are important
for specifying fibroblast fates (10). Not only
is there tremendous diversity in the vari-
ous tissue microenvironments that contain
fibroblasts, but as Plikus et al. show, these
niches can change dramatically during in-
jury and disease. Fibroblasts in tissues such
as vessels, tendons, and skin are normally
tasked with forming the connective layers
of cells and extracellular matrices that hold
soft tissues together. However, injuries dis-
rupt this normal signaling arrangement
and expose fibroblasts within the wound
niche to infiltrating hematopoietic cell
lineages, such as macrophages, and to in-
flammatory cytokines that can modify their
activity. In addition, Plikus et al. show that
fibroblasts can respond to BMP that is re-
leased by nonhematopoietic epidermal lin-
eages in regenerating cutaneous wounds.
It is also possible that fibroblast migration
triggered by injury exposes fibroblasts to
new sources of signals that they are normally not subjected to, which could be conducive to fibroblast plasticity (10).
What is the true extent of fibroblast
plasticity and how does it relate to wound
regeneration? Due to the great number of
mitigating factors, single-cell approaches
are indispensable for deconvoluting the
complexities that involve both the intrin-
sic and extrinsic determinants of fibro-
blast fates. Genetic tools can enable clonal
tracing of single differentiating fibroblast
lineages in an animal model to evaluate
the frequency of multipotent lineage com-
mitment in the normal setting and upon
injury. For example, “Rainbow” and “Con-
fetti” mice are genetically engineered to al-
low the fluorescent labeling and distinction
of individual and adjacent cells. Barcoding
techniques can also enable clonal tracing of
single differentiating fibroblast lineages in
situ (11, 12). Because distinct fibroblast lin-
eages arising from different developmental
origins can colocalize to the same tissue,
it may be necessary to use newer versions
of genetic drivers such as “split-Cre” sys-
tems that are triggered by simultaneous
activation of two specific promoters rather
than one (13). Intravital imaging used in
conjunction with clonal-lineage tracing
systems could provide powerful evidence
for fibroblast plasticity while also tracking
other cells in the injury’s microenviron-
ment, including infiltrating macrophages
and migrating fibroblasts (14). Prospective
isolation techniques could then be em-
ployed to isolate the specific fibroblast or
fibroblast stem cells in keloids, for exam-
ple, for functional and single cell molecu-
lar characterization so as to determine the
mechanistic basis of plasticity (6).
The findings of Plikus et al. have broad
ramifications for the clinical treatment of
fibrotic disorders, including scarring, organ
fibrosis (such as lung, liver, or kidney), visceral adhesions, scleroderma, myelofibro-sis, and perhaps even aging by suggesting
that fibrotic lesions could be transformed
into a more innocuous tissue type such as
fat if they cannot be removed or prevented
from forming directly. At the same time,
their results also touch on key questions
underlying mesodermal tissue plasticity
with important implications for a broad
array of topics ranging from mechanisms
of cellular reprogramming, as in induced
pluripotent stem cells and the epithelial-mesenchymal transition, to the identity of
adult mesodermal stem cells and the plasticity of mesodermal populations, including myofibroblasts (15). j
1. G. C. Gurtner, S. Werner, Y. Barrandon, M. T. Longaker,
Nature453, 314 (2008).
2. C. K. Sen et al ., Wound Repair Regen. 17, 763 (2009).
3. M. V. Plikus et al ., Science355, 748 (2017).
4. E. R. Zielinsetal.,Regen.Med.9, 817 (2014).
5. M. Ito et al., Nature 447, 316 (2007).
6. C. K. Chan etal .,Cell 160, 285 (2015).
7. R. R. Driskell et al ., Nature 504, 277 (2013).
8. Y. Rinkevich et al ., Science 348, aaa2151 (2015).
9. H. Y. Chang etal .,
10. T. J. Shaw, P. Martin, Curr. Opin. Cell Biol. 42, 29 (2016).
11. E. Roy, Z. Neufeld, J. Livet, K. Khosrotehrani, Stem Cells 32,
12. R. Lu, N. F. Neff, S. R. Quake, I. L. Weissman, Nat.
Biotechnol. 29, 928 (2011).
13. R. Beckervordersandforth et al., Cell Stem Cell 7, 744
14. R. P. Barretto et al ., Nat. Med. 17, 223 (2011).
15. I. R. Murray et al ., Cell Mol. Life Sci. 71, 1353 (2014).
Wounded epidermis New hair germ
adipocytes Hair follicle
Day 0 Days 12 to 14
Days 14 to 19
Days 21 to 28
New wound Scab Wound closure
Hair follicle regeneration
Adipocycte regeneration via lineage
reprogramming of myofbroblasts
From fibroblasts to fat
A mouse model of epidermal wound healing points
to the plasticity of local myofibroblasts. These cells
stimulate hair follicle development, which in turn,
stimulates their reprogramming to adipocytes. This
decreases fibrosis and pathologic scarring.