Medical Hypotheses 76 (2011) 343346

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

A novel promising therapy for skin aging: Dermal multipotent stem cells against
photoaged skin by activation of TGF-b/Smad and p38 MAPK signaling pathway
Jianqiao Zhong a,b, Nianfang Hu a, Xia Xiong b, Qirong Lei b, Li Li a,
a
b

Department of Dermatology, West China Hospital, Sichuan University, Chengdu 610041, China
Department of Dermatology, Afliated Hospital of Luzhou Medical College, Luzhou 646000, China

a r t i c l e

i n f o

Article history:
Received 27 April 2010
Accepted 22 October 2010

a b s t r a c t
Skin photoaging, the most common skin damage, is caused by chronic UV irradiation. It is involved in the
reduction, aging and apoptosis of broblasts (FBs) as well as the blockage of transforming growth factorbeta (TGF-b)/Smad and p38 mitogen-actived protein kinase (MAPK) signaling pathways. Dermal multipotent stem cells (dMSCs) are a population of adult stem cells derived from dermis in recent years. It has
been conrmed that dMSCs can activate or differentiate into FBs to participate in wound healing by producing and expressing TGF-b and other cytokines. Considering the mechanism of skin photoaging and the
role of dMSCs, we hold a hypothesis that dMSCs may be applied in skin photoaging by activating TGF-b/
Smad and p38 MAPK signaling pathways, and then stimulating FBs to secrete and synthesize collagen or
elastin, heightening the extracellular matrix, nally eliminating wrinkles and strengthening skin elasticity. These would provide a novel approach for anti-skin photoaging.
2010 Elsevier Ltd. All rights reserved.

Introduction
Skin photoaging, resulting from cumulative sun exposure, is
characterized by dryness, roughness, laxity, dyschromia, telangiectasia, wrinkles, and irregular pigmentation [1,2]. It has been shown
to have substantial impacts not only on patient cosmetic trouble,
but also on patient psychological and physical health [3,4].
Although there are many approaches for skin photoaging such as
topical agents, dermabrasion, optical therapies, broblasts (FBs) or
cytokines injecting, and so on, these measurements are restricted
by the risk of signicant side effects or a prolonged downtime or a
transitory efcacy and remain unsatisfactory so far [1,58].
Recently, some reports have shown that epidermal stem cells, mesenchymal stem cells or adipose-derived stem cells have a role of
anti-aging [9,10]. However, the former are unipotent only to differentiate into epidermis, while the latter two posses scarce resource,
poor integration with the host and a potential to develop into the
original tissue [911]. For these reasons, these therapies are also
limited in practice. Consequently, it is extremely important to nd
a new way to treat skin photoaging. Dermal multipotent stem cells
(dMSCs), a population of adult stem cells isolated from dermis, can
differentiate into cells with phenotypic properties of FBs, osteocytes
and adipocytes in specic inducing media [12,13]. Currently, studies about dMSCs primarily focus on skin-tissue-engineering, tissue

Corresponding author. Address: Department of Dermatology, West China

Hospital, Sichuan University, Wai nan guo xue xiang 37, Chengdu 610041, China.
Tel.: +86 13908205858, +86 18980601692; fax: +86 28 85422363.
E-mail address: lyli7632@hotmail.com (L. Li).
0306-9877/$ - see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2010.10.035

defects compensation, wound repair and diabetes mellitus, etc.,

but hardly on skin photoaging [1416]. Considering that dMSCs
are abundantly accessible and immune privileged with a powerful
proliferation capacity and multi-lineage differentiation potential,
we highly hypothesize that dMSCs will provide hope for the treatment of skin photoaging.
Pathogenesis of skin photoaging
At present, it is thought that the pathogenesis of skin photoaging is closely associated with FBs and transforming growth factorbeta (TGF-b)/Smad [1719]. It primarily involves the reduction,
aging and apoptosis of FBs induced by UVB/UVA radiation
[18,20,21]. In this process, TGF-b/Smad signaling transduction
pathway plays a critical role [18,22].
TGF-b, a key regulator in the extracellular matrix (ECM), with
TGF-b receptor and Smad protein jointly constitute TGF-b/Smad
signaling pathway. Through this signaling pathway, TGF-b can
facilitate collagen I/III and elastin synthesis in FBs, repress matrix
metalloproteinases (MMPs) activity, enhance bronectin (FN)
expression, decrease collagen bers degradation and heighten
ECM [18,22]. Furthermore, TGF-b can also activate p38 mitogenactived protein kinase (MAPK) to stimulate FBs proliferation, restrain FBs apoptosis, and improve the expression of collagen bers,
elastic bers and FN [23].
However, the two signaling pathways are apparently inhibited
in chronic skin photoaging [1719,22,24]. Studies in vivo indicated
that UVA1/UV could remarkably reduce TGF-b1 or TGF-b1 receptor
expression and block Smad3/4/7 signaling pathway [19,24]. By

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J. Zhong et al. / Medical Hypotheses 76 (2011) 343346

inhibiting TGF-b/Smad and p38MAPK signaling pathway, UVB/UVA

contributed to encourage FBs reduction or apoptosis, promote FN
fall-off, increase MMPs expression and decrease collagen I expression, which ultimately lead to alterations in dermal morphous and
function [1821,24,25]. When low-dose UVB irradiated skin, activator protein-1(AP-1) was activated through suppression of TGFb-mediated p38MAPK signaling pathway, which was followed by
excessive expression of MMP-1, 9kD gelatinase and stromlysin-1,
accordingly these enzymes disorganized skin collagen, degraded
ECM and resulted in skin photoaging [17,19,26,27]. The primary
pathogenesis process of skin photoaging is shown in Fig. 1.

The role of dMSCs and its relation with TGF-b

Derived from dermis, dMSCs or skin-derived precursors (SKP)
possess self-renewal and multi-lineage differentiation capacities.
They can synthesize nestin, bronectin and vimentin as well as
other marker proteins and exhibit differentiation-inducing ability
to transform into fat, bone, muscle, liver and nerve cells [12,13].

Due to their multipotency, dMSCs can activate or differentiate

into FBs in a special condition to induce new collagen and elastin
synthesis, and then accelerate wound healing and tissue repair.
Further studies have shown that the mechanism of dMSCs activation or differentiation into dermal FBs were through expressing
TGF-b and other growth factors [28]. The production and secretion
of TGF-b and cytokines have been reported as an essential function
of dMSCs [29]. Previously, Shi indicated that dMSCs can participate
in the healing process of skin wounds via topical implantation or
systemic infusion of dMSCs to promote the hematopoietic recovery
in irradiated rats [30,31]. Recently, studies showed that dMSCs
have a wound healing effect through the production of TGF-b
and other cytokines [28]. TGF-b and the cytokines have the ability
to activate FBs, increase the proliferation rate of FBs and mediate
the secretion of collagen from FBs. After dMSCs were transplanted
into wound location, they could secrete and express a series of
cytokines and ECM molecules to enhance the proliferation of FBs.
These cytokines consist of TGF-b, IL-3, IL-6, IL-15, VEGF, PDGF,
HGF, ICAM-1, VCAM-1 and FN, among which TGF-b is the most potent stimulator [28].

Fig. 1. The primary pathogenesis process of skin photoaging. UV radiation can down-regulate the expression of TGF-b or TGF-b receptor and result in the reduction or
apoptosis of FBs as well as the activation of AP-1 by blocking TGF-b/Smad and p38MAPK signaling pathways [1721,26,27]. The changes of FBs and AP-1 respectively increase
the expression of MMPs, Cathepsin G and 9kD gelatinase, etc., which can lead to collagen or elastin production decreasing as well as collagen and ECM breakdown increasing
[2427]. Ultimately, these may contribute to skin photoaging presentation. FBs, broblasts; TGF-b, transforming growth factor-beta; MAPK, mitogen-actived protein kinase;
FN, bronectin; AP-1, activator protein-1; MMPs, matrix metalloproteinases; ECM, extracellular matrix. "increase; ;decrease; Hblocking; Iapoptosis.

J. Zhong et al. / Medical Hypotheses 76 (2011) 343346

On the whole, dMSCs have effects on FBs by producing and

expressing TGF-b to stimulate FBs proliferation or differentiating
into FBs, suggesting that dMSCs can be used for the treatment of
wound healing and skin aging.
Hypothesis
As their multi-lineage developmental plasticity, dMSCs have
been widely studied and partly applied in some clinical diseases
other than skin photoaging. Given that TGF-b, TGF-b/Smad signaling pathway and FBs involve in skin photoaging and dMSCs can express TGF-b to affect FBs, it is hypothesized that dMSCs may be
fairly useful in anti-skin photoaging by activation of TGF-b/Smad
signaling pathway. The hypothesized process of dMSCs against
skin photoaging is shown in Fig. 2. This hypothesis formulation is
based on the following points: (1) TGF-b/Smad and p38MAPK signaling pathways are inhibited in skin photoaging [1719,22,24],
(2) Skin photoaging also involves the reduction, aging and apoptosis of FBs, as well as change of collagen and elastin [17,20,21], (3)
dMSCs have a multi-lineage differentiation capacity so that they
can differentiate into FBs in a particular condition [12,13], (4)
dMSCs can stimulate FBs proliferation by producing and expressing
TGF-b [28], (5) It has been demonstrated that dMSCs can be successfully transplanted into the wound site and join in the course
of wound healing by expressing TGF-b to activate or recruit FBs
[28].

345

Clinical signicance
Skin photoaging and anti-skin aging have been constantly the
focus of research in cosmetic dermatology. Despite various invasive or noninvasive treatments used to the reversal of skin photoaging, these therapies are conned to apply further by transitory
efcacy, rare resource and heterologous differentiation. As dMSCs
origin from the dermis with homology, multipotency and afuent
source, they may be used in skin photoaging to facilitate collagen
and elastin composition and heighten the ECM. The use of dMSCs
may have an anti-aging effect mainly mediated by activating
TGF-b/Smad and p38MAPK signaling pathways, and then stimulating FBs proliferation or differentiating into FBs and prohibitting
MMPs release. Therefore, the application of dMSCs would make it
possible to reduce wrinkles, strengthen skin elasticity and regenerate skin. In addition, exchange and co-activity among dMSCs and
other cells could make a global activation and rejuvenation of the
skin, including sufcient correction of wrinkles and laxity.
Future research
To test this hypothesis and clarify the role of dMSCs for skin
photoaging, further progress of the research in this area is required
in animal modes and clinical cases. It will be helpful to further
identify the regeneration mechanisms of human skin and be possible to apply dMSCs in medical and cosmetic procedures. Before
clinical trials, animal experiments should rstly be carried out, that
is, the effect of dMSCs in skin photoaging and the mechanisms for
dMSCs anti-skin photoaging will be investigated by both experiments in vivo and in vitro. On one hand, wrinkles will be induced
in nude mice after an eight-week UVA/ UVB irradiation and the
antiwrinkle effect will be investigated by the subcutaneous injection of dMSCs. On the other hand, mechanisms for dMSCs antiaging will be studied further by using a conditioned medium of
dMSCs to co-culture dMSCs and FBs under intervention of UVA/
UVB. If experimental results are practical, a clinical trial will be further carried out through placebo-controlled study. These may offer
a scientic basis for further study on dMSCs in the clinical application. Once these concerns are claried, it is rmly believed that
dMSCs could hold great promise for clinical applications in skin
photoaging and regeneration in the near future.
Conict of interest statement
We make clear that we have no competing nancial interests
with other people or organizations which may improperly affect
our study. There is no benets in any form have been or will be received from a commercial party related directly or indirectly to the
subject of this article.
Acknowledgements
We thank Qintong Li, MD, Qinglian Wen, MD, Luzhou, China,
and Xiangyu Zhou, MD, Luzhou, China, for helpful discussion on
this manuscript. We also thank anonymous referee for his/her very
helpful comments, which remarkably improved the quality of this
paper.
References

Fig. 2. The hypothesized process of dMSCs against skin photoaging. Due to

expression TGF-b [28,29], dMSCs can stimulate FBs proliferation or differentiate
into FBs through activating TGF-b/Smad and p38MAPK signaling pathways
[18,22,23]. In turn, FBs may abundantly produce and secret collagen or elastin as
well as enhance ECM, which nally lead to skin rejuvenation and regeneration.
"increase; ;decrease; activating.

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