Commentary on ‘Identity noise and adipogenic traits characterize dermal fibroblast
aging’, by Salzer et al., Cell, 2018.
3
The greater longevity achieved by our society has brought the current research to
give a particular interest on understanding the mechanisms underlying ageing, as age
is the major risk factor for many pathologies, including cancer, neurodegeneration,
and cardiovascular disease.
1
Ageing can be defined in general terms as a time-dependent structural and functional
decline and the deterioration of the skin is one of the most apparent signs of it.
The dermis, that is one of the three layers constituting the skin, is populated by
fibroblasts that synthesize and secrete collagens and other matrix proteins that maintain
the skin architecture and confer elasticity, resistance and strength to the tissue.
2
During ageing the dermis is characterized by loss of cellularity and extracellular
matrix (ECM) remodelling.
2
,
3
Even though dermal fibroblasts have been widely used as an in vitro model of cellular
ageing for decades, the molecular mechanisms leading to these cells ageing in vivo
are poorly understood.
2
Dermal fibroblasts derive from mesenchymal progenitors and can be distinguished in
the newborn dermis in four types: the papillary fibroblasts, which are restricted
in the upper dermis, the reticular fibroblasts that are spread throughout the ECM
dense lower dermis and two Sca1+ pro-adipogenic types, which are located in the lower
reticular dermis.
4
However, in adulthood the cell surface epitopes that discriminate among these types
of fibroblasts are lost and this compromises the possibility to investigate whether
the adult dermis still contains these lineages.
4
Salzer et al., in a very recent issue of cell, addressed these gaps in our knowledge
by means of bulk- and single-cell transcriptomic analyses and long-term lineage tracing.
They found that during ageing dermal fibroblasts have a less well-defined identity,
as the transcriptome features that define clusters in young cells become blurry with
age, and paradoxically old fibroblasts acquire adipogenic traits reminiscent of newborn
pro-adipogenic fibroblasts.
3
The intrinsic rate of skin ageing in every organism can be hugely affected by extrinsic
factors, such as exposure to ultraviolet light; since dermal fibroblasts are long-lived
cells that continuously accumulate damage, they are a preferred model to study extrinsic
ageing at the cellular level.
2
However, although many studies display the beneficial effects of calorie restriction
(CR) without malnutrition on longevity and age-related diseases, such as obesity,
diabetes mellitus, cardiovascular disease, and cancer, the consequences of dietary
interventions on dermal fibroblasts during ageing had been unexplored so far.
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,
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Hence, Salzer et al.
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evaluated whether they could modulate the aged fibroblasts phenotype by feeding mice
with a CR diet or a high fat diet (HFD). Interestingly, they found that CR could prevent
the loss of papillary characteristics and the gain of adipogenic traits in old fibroblasts
and that the transcriptome of adult dermal fibroblasts isolated from HFD-fed mice
positively correlated with the one of old fibroblasts; these results indicate that
CR and HFD could respectively delay and accelerate the ageing processes of these cells.
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Hence, they suggested loss of cell identity as a mechanism underlying cellular ageing
and dietary intervention as a possible therapeutic strategy to slow down skin ageing.
This study that employs state of the art techniques to decipher fibroblast ageing
in vivo has surely a high impact in the poorly understood field of skin dermis ageing;
but, I believe that it also has a broader relevance comprising the cardiovascular
field. For instance, if loss of cell identity is a possible mechanism underlying ageing,
this could also explain what occurs in the aged heart and vessels, as cardiac fibroblasts
and vascular smooth muscle cells (VSMC), which similarly to dermal fibroblasts play
crucial structural and functional roles in their tissues, are more prone to phenotypic
shifts that lead to age-related dysfunctions, such as cardiac fibrosis and vascular
calcification, respectively.
7–9
Interestingly, both myofibroblasts and VSMC transdifferentiating towards an osteochondrogenic
lineage display altered expression of ECM-related genes and increased expression of
pro-inflammatory factors
9–12
; similarly, Salzer et al.
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observed that old fibroblasts, along with acquiring the newly identified feature of
cell identity loss, exhibited these two typical characteristics of aged cells, as
well as they up-regulated the expression of genes involved in adipogenesis. Although
VSMC grown in apidogenic media develop adipocyte markers, it still has to be determined
whether these cells, as well as cardiac fibroblasts, are able to acquire these adipogenic
traits during ageing and, if so, it would be interesting to evaluate which are the
consequences of this shift on the cardiovascular system.
9
Intriguingly, the same cutting-edge approach of combining single-cell RNA sequencing
and lineage tracing has been employed to unveil similar mechanisms in cardiovascular
diseases. Indeed, Kretzschmar et al.
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in a very recent study observed that a subpopulation of activated fibroblasts acquires
a neonatal-like gene expression profile in response to ischaemic injury; it is thus
tempting to speculate that this cellular attempt of rejuvenation towards a neonatal-like
state may be an adaptive mechanism that at least fibroblasts could adopt to respond
to different insults, such as cardiac damage and skin ageing. Moreover, Dobnikar et
al. investigated the transcriptional signatures of VSMC in healthy and atherosclerotic
vessels and found a subpopulation of lineage-traced VSMC positive for the progenitor
cell marker Sca1 that they suggested to be involved in the vessel response to injury;
they also observed Sca1 up-regulation in VSMC exposed to stimuli that are known to
induce the phenotypic switching of these cells.
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However, whether the loss of identity that may enable cells to acquire a stem/progenitor-like
phenotype, possibly as an adaptive response to the age-related stem cell exhaustion,
occurs in cardiac fibroblasts or VSMC during ageing still remains to be elucidated.
Hence, the future research that aims to decipher the molecular and cellular mechanisms
controlling cardiovascular ageing and age-related diseases should reckon with the
findings described by Salzer et al., that may be even extended to other organs and
tissues.
Conflict of interest: none declared.
Funding
This work was supported by the British Heart Foundation (FS/16/15/32047).