fibroblasts: what's new in cellular biology?

Fibroblasts: what’s new in cellularbiology?

A Le Pillouer-Prost

Fibroblast cells

Fibroblasts are multipotent cells of mesodermal origin and

source of the entire extra cellular matrix (ECM), a hydrated

gel composed of: structural proteins, glycosaminoglycans

and glycoproteins, adhesive molecules, and various cyto-

kines (growth factors, notably fibroblast growth factors-

FGFs, interleukines-IL, interferons-IFN and so on),

prostaglandins and leukotrienes. By these syntheses and

cell-to-cell, cell-to-cytokine interdependencies, fibroblasts

contribute much to the fibroblast-keratinocyte-endothe-

lium complex that maintains the integrity and youth of

skin1,2 (Figures 1 and 2). The study of their cellular biology

has seen an extraordinary expansion in the last few years in

various research fields.

The question of whether all fibroblasts are identical

or whether they are heterogeneous has been raised3 and

differences between papillary and reticular fibroblasts have

been proposed (for example, FGF-7 expression is markedly

increased in fibroblasts underlying the epidermal layer). It

can be very important for therapeutic effects, notably for

laser treatments. The depth of photo irradiation will allow

the stimulation of some specific fibroblast phenotypes.

Fibroblast senescence

During senescence, numerous changes are observed in gene

expression and cellular morphology. Telomere length has

Author:A Le Pillouer-ProstDermatologist, Marseilles, France

Keywords:

fibroblasts – cytokines

This paper briefly examines thefibroblast network with particularemphasis on the exceptionally com-plex pattern of specific interactionsand their effects on dermal integrityand homeostasis regulation systems.It will be some time before we

have a full understanding ofthe cellular biology mechanismsinvolved in the operation of lasers,flashlamps, peels, mechanical derma-brasions, fillers or topicals onthe skin. J Cosmetic & Laser Ther 2003;

5: 232–238

Figure 1

Keratinocyte-fibroblast interdependencies.

Figure 2

General scheme for FGF/cell interactions.

J Cosmetic & Laser Ther 2003; 5: 232–238# J Cosmetic & Laser Ther. All rights reserved ISSN 1476-4172DOI: 10.1080/14764170310021869 232

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been proposed as a counting mechanism for the number of

cell divisions that controls cellular senescence. Telomeres

are specialized structures at the end of chromosomes which

function in chromosome stability, positioning, replication

and meiosis. Telomere DNA shortens with an increased

number of cell divisions and the limit of the proliferative

life span of normal cells occurs when the length reaches

around 5 kb. We still do not have enough evidence for the

mechanism monitoring telomere length during cell aging,

but telomere binding proteins including TRF 1 or TRF 2

are possible candidates for the monitoring molecules. It

was proved that telomere reduction not only determines

the limit of cell proliferation but also modifies earlier the

expression level of functional genes such as growth factors

and cytokines.4 In the in vitro aging human fibroblasts,

telomere shortening induces a change in the expression

level of various genes which occurs earlier than that of

genes that halt the cycle. A particularly interesting study5

evaluated the expression levels of several genes encoding

growth factors and cytokines and the possible recovery

from this senescence by telomere elongation after intro-

duction of hTERT (human telomerase reverse transcrip-

tase) cDNA. The results classified the genes in four groups:

(1) genes whose expression level decreases with prolifera-

tive aging and are correlated with telomere length,

keratinocyte growth factor and insulin-like growth factor-

II; (2) genes whose expression level decreases with

proliferative aging and are not correlated with telomere

shortening, hepatocyte growth factor; (3) genes whose

expression level is high in senescent cells and is controlled

by growth conditions, follistsatin and HB-EGF; (4) genes

whose expression level does not change with proliferative

aging or telomere elongation, fibroblast growth factors

(FGF 1 and 2), vasculo-endothelial growth factor, bone

morphogenetic protein-3 and amphiregulin. A recent

report6 shows that aging fibroblasts present reduced

epidermal growth factor (EGF) responsiveness due in fact

to preferential loss of EGF receptors.

In senescent fibroblasts, tissue-specific expression of

various proteins (especially p14ARF and p16INK4), involved

in RNA metabolism is decreased (notably hnRNP A1 and

A2, and splicing factors) and the myriad changes observed

are potentially explained by alterations in the RNA post-

transcriptional processing.7 It has also been demonstrated

that the age-associated decrease in the repair of UV-

induced DNA damage results at least in part from

decreased levels of mRNA levels and proteins that

participate in the nucleotide excision repair process.8

A recent study (in situ hybridization and immunohisto-

chemical stain) compared the level of type I procollagen

and the activity of metalloproteinase 1 and 2 in photoaged

and naturally aged skin. The results show that the natural

aging process decreases collagen synthesis and increases the

expression of matrix metalloproteinases, whereas photo

aging results in an increase of collagen synthesis and greater

matrix metalloproteinase expression.9 Another study10

concluded that fibroblasts from photoaged and sun

protected skin are similar in their capacities for growth

and type I procollagen production, but the accumulation of

partially degraded collagen observed in photodamaged skin

may inhibit, by an as yet unidentified mechanism, type I

procollagen synthesis. The results of a biochemical study

published by Mays11 demonstrate that age-related altera-

tions in collagen and total protein metabolism of skin

fibroblasts in culture were similar to those reported

previously for skin in vivo, suggesting that for studies

fibroblasts in culture provide an appropriate material.

Cytokines and cytokine receptors

Cell-to-cell communications are assumed by direct mem-

brane contacts and a very complex network of soluble

factors and their membranous receptors called cytokines

(interleukins, interferons, colony stimulating factors,

tumour necrosis factor family, growth factors and

others). Some of their principal characteristics are:

production by several cell types; various target cell

populations; broad spectrum and redundancy; autocrine,

paracrine, juxtacrine and endocrine modes of action; action

by specific membranous cellular receptors expressed to the

surface target cells; cascade induction with up or down-

regulation for other cytokines or themselves (feedback

loops); multiple interactions with other local components.

The complexity of the network is majored by several

level possibilities of modulation: synthesis after cell

activation, receptor bindings, and various types of

transduction signals (tyrosine kinases, signal transducer

and activators of transcription - STAT, gamma activated

sequences - GAS, Ras and MAP-kinases, cytokine inducible

SH2-CIS, etc), soluble receptors (antagonists or conversely,

agonists, carriers or chaperones). For fibroblasts, the main

implicated cytokines are platelet derived growth factors

(PDGFs), latent and active transforming growth factor-beta

1 (TGF-beta 1), tumour necrosis factor alpha (TNF-alpha),

interleukin-1 beta (IL-1beta), fibroblast growth factors

(FGFs) and IL-6, IL-10. PDGF is released by platelets,

activated macrophages, endothelial cells, fibroblasts and

smooth muscle cells and is a major player in regulating

fibroblast and smooth muscle cell recruitment and

proliferation through PDGF specific receptor-ligand inter-

actions. It also up-regulates protease production.

TGF-beta 1 has undoubtedly the broadest but the most

controversial effects. The paradoxical actions of TGF-beta 1

depend upon the state of the cell and the context of action.

During wound healing TGF-beta 1 stimulates matrix

synthesis and deposition by inducing fibroblasts to

synthesize collagen, fibronectin, elastin and glycosamino-

glycans. TGF-beta 1 also modulates the expression of

proteases and their inhibitors, acts as a chemo attractant

for monocytes and fibroblasts, causes the differentiation of

fibroblast into myofibroblasts and enhances neovascular-

ization. TGF-beta 1 is secreted as a latent complex and the

mechanisms by which TGF-beta 1 is activated in vivo have

not been fully elucidated. Roles of plasmin or cathepsin D

or extreme conditions of pH and heat (80‡C for 10min)

and detergents have been reported. TNF-alpha is an anti-

tumoral, immunologic, embryogenic, hematopoietic and

pro-inflammatory cytokine. On fibroblasts, TNF-alpha

stimulates PGE2 and collagenases, reduces collagen and

Fibroblasts: what’s new in cellular biology? 233


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fibronectin synthesis and induces IL-6, IL-8 and granulo-

cyte monocyte-CSF. IL-1 has a multitude of actions – it

promotes fibroblast proliferation via its various target cells

(lymphocytes, endothelial cells, fibroblasts, macrophages

and monocytes) and their cytokines (PDGF, TGF, TNF, IL,

CSF, IFN, etc). For the other interleukins: IL-2 and 15,

fibroblast proliferation; IL-4, fibroblast inhibitor; IL-8,

fibroblast chemo attraction; IL-11, stimulation of TIMP-s

de novo synthesis (metalloprotease tissular inhibitors).

Gap junctional intercellularcommunication (GJIC)

Gap junction channels are important in coordinating the

activities of electrically active cells. They allow free cell-to-

cell diffusion of low molecular weight molecules (,1 kDa),

such as ions, water, sugars, nucleotides, amino acids, fatty

acids, small peptides, drugs and carcinogens. They also

have been suggested to play a regulatory role in many

processes (growth control, development and differentia-

tion, synchronisation and metabolic regulation).

Matrix metalloproteinase (MMPs)modulation of cytokines

MMPs are members of a family of at least 15 Zn-dependent

endopeptidases, secreted by leukocytes, particularly macro-

phages, and involved in tissue remodeling and aging. In

addition to modifying extra cellular matrix proteins by

functioning in enzyme cascades, they also act as regulatory

molecules for cytokines and cytokine receptors, growth

factors and adhesion molecules. Much of the early

literature suggested that each MMP had its own particular

substrate. This concept led to the use of substrate-focused

nomenclature for MMPs such that the collagenase broke

down intact fibrillar collagens, gelatinases degraded

denatured collagen, and metalloelastase attacked elastin.

It is now recognized that MMPs usually degrade multiple

substrates, with considerable substrate overlap between

individual MMPs. For example, interstitial collagenase

(MMP-1) is capable of degrading casein, gelatine, alpha-1

antitrypsine, myelin basic protein, L-selectin, pro-TNF and

IL-1 beta and pro-MMP-2 and -9; 72-kDa gelatinase

(MMP-2) can degrade fibrillar collagen, elastin, IGF-

binding proteins, FGF receptor and can activate MMP-1,

-9 and -13. Moreover, tissue inhibitors of metalloprotei-

nases (TIMPs) are a group of inhibitors of activated matrix

metalloproteinases, such as gelatinase and collagenase, that

can help to control extra cellular matrix metabolism and

deposition by connective tissue cells. Both expressions of

MMPs and TIMPs are regulated by various cytokines in

dermal human fibroblasts. For example, TIMP-2 protein

and its mRNA expression are induced by IL-412 in a dose-

and time-dependent manner by a transcription mechanism

(role of the p38 mitogen-activated protein kinase - p38

MAPK). All these phenomena are very complex and

intricate.

Cell-to-cell fibroblast interactions

Keratinocytes

The wound healing process concludes with down regula-

tion of fibroblast activity by regenerating epidermis. This

keratinocyte-mediated suppression is a soluble and stable

factor, identified as IL-1 alpha13 which was confirmed to

inhibit the connective tissue growth factor mRNA expres-

sion in fibroblasts. The main keratinocyte-fibroblast

interactions are summarized in Figure 1.

Fat cells

In a co-culture system, fat cells promote the proliferation

and differentiation of keratinocytes and conversely inhibit

the proliferation of dermal fibroblasts, effects mediated by

other cytokines than leptin, TNF-alpha or IGF-II.14

Mast cells

The ability of mast cells to express and/or secrete several

growth factors of the FGF family as well as heparin-binding

EGF directly or indirectly by fibroblast stimulation was

demonstrated recently.15 From another source,16 mediators

produced by the mast cells play a major role in the

regulation of myofibroblast differentiation (expression of

alpha smooth muscle actin) and function (capacity to

contract a collagen matrix). To characterize the individual

contribution made by specific mast cell products, they

examined the effect of histamine, TNF alpha and tryptase.

Histamine induced a clear increase in alpha-smooth muscle

actin expression, but it did not appear to stimulate

fibroblast contraction; TNF alpha had no effect and

purified human tryptase induced alpha-smooth muscle

actin expression. Moreover, tryptase inhibitors reduced that

response and also eliminated the ability of mast cells to

stimulate fibroblast contraction, suggesting that tryptase

secreted by mast cells may be one of the active mediators.

T cells

Human dermal fibroblasts undergo activation and secrete

cytokines when co cultured with T-cells. Population with

strong human dermal fibroblast activity consists essentially

of cells with natural killer surface marker phenotype.

Addition of these cells to human dermal fibroblasts results

in rapid increase of intracellular free calcium concentration

(early cell activation signal) and upregulation of mRNA

encoding for the inflammatory cytokines IL-1 beta, IL-6,

IL-8 and MCP-1.17

Examples of cell-to-cytokine fibroblastinteractions

TGF beta 1

TGF beta 1 is a major and multifunctional cytokine

involved in matrix deposition and remodeling (synthesis

stimulation: collagens, fibronectin, proteoglycans; inhibi-

tion of the degradation: metalloprotease inhibition,

234 A L Pillouer-Prost


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stimulation of metalloprotease inhibitors). Its activity varies

on time and substrate dependent pathways.

IL-10

IL-10 is a cytokine with many regulatory functions. In

particular, IL-10 exerts neutralizing effects on other

cytokines. Recent reports18 suggest that IL-10 regulates

not only immunocytes but also collagen and collagenase

gene expression in fibroblasts and elicits the way of doing

that: they demonstrate that IL-10 down regulates the

crucial fibrogenic cytokine TGF beta.

IL-4

Through its role on TIMP-2.12

IL-17

IL-17 enhances the TNF-alpha-induced IL-6 and IL-8

secretion in human colonic sub epithelial myofibroblasts.19

Fibroblast growth factors (FGFs) andtheir receptors

There are nine identified members of the FGF family and

even a larger variety of specific high-affinity receptors. This

leads again to an exceptionally complex pattern of specific

interactions and specific effects on cells. There is an

unimaginable variety of FGF receptors (four distinct

complex variant isoforms, glycosaminoglycans co-receptors,

antagonist soluble forms, see Table 1), FGF receptor

bindings (heparan sulphate-like), signal transductions

(tyrosine kinase), possible nuclear localizations. The FGFs

play major roles in an enormous number of functions

(haematopoiesis, development, wound repair, tumour

angiogenesis) and the name of FGF is misleading. While

some FGFs do indeed, initiate fibroblast proliferation, they

induce proliferation of many other cells as well, and their

actions are more general than proliferation (see Table 2).

The basic FGF (bFGF) is mitogenic, inhibits collagen

production and stabilizes cellular phenotypes.

Apoptosis/heat shock proteins (HSPs)

Apoptosis

Apoptosis is a controlled cell disassembly, also called

‘‘programmed cell death’’, distinguished from necrosis by

the absence of an inflammatory response. The cytosolic

aspartate-specific Proteases, called CASPases, are respon-

sible for the deliberate disassembly of a cell into apoptotic

bodies. Removal of a cytokine required for cellular viability

leads to the following sequential events: loss of kinase

FGF-receptors Specificity Cells expressing (partial list)

FGF-R1 variant IIIb FGF-1 Fibroblasts, endothelial, certain epithelial, vascular smooth muscle, lymphocytesFGF-R1 variant IIIc FGF-1,2,4 Macrophages, hematopoietic progenitors, numerous tumor

FGF-R2 variant IIIb FGF-1,2,7 Epithelial

FGF-R2 variant IIIc FGF-1,2,4 Fibroblasts, endothelial,vascular smooth muscle, oligodendroglia, astrocytes,

hematopoietic progenitors, lymphocytes, macrophages, carcinoma and sarcomaFGF-R3 variant IIIb FGF 1,2 Epithelial, keratinocytes

FGF-R3 variant IIIc FGF 1,4,9 (2?) Fibroblasts, monocytes, vascular endothelial, hematopoietic progenitors

FGF-R4 FGF 1,2,6 Embryonic and multipotential stem

Table 1

Complexity of FGF receptors.

FGF Where produced Major biological functions

FGF-1 Smooth muscle cells, endothelial cells, neurons, fibroblasts,

hepatocytes, macrophages, keratinocytes

Wound repair (major roles during granulation

and reepithelialization)

FGF-2 Retinal cells, astrocytes, T-cells, platelets, keratinocytes, fibroblasts,smooth muscle cells, macrophages,

endothelial cells, neurons, embryonic meso and ectoderm

Hematopoiesis, stromal cells, wound repair(granulation and reepithelialization), tumor

angiogenesis

FGF-3 Embryonic tissue, breast carcinoma Embryogenesis

FGF-4 Embryonic tissue EmbryogenesisFGF-5 Embryonic tissue, adult muscle, Kaposi’s sarcoma cells Embryonic ectoderm

FGF-6 Skeletal muscle Skeletal muscle development, myoblast proliferation

FGF-7 Fibroblasts (markedly in FB underlying the epidermal layer),smooth muscle cells, embryonic mesenchymal cells

Branching of bronchi in interaction with FGF-2

FGF-8 Embryonic ectoderm (mouse only) Mesenchymal proliferation (length of the limb)

FGF-9 Glioma cell line

Table 2

Fibroblast growth factors (FGFs).



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activity; dephosphorylation of Bad (or some other

regulator); Bad binding; loss of normal mitochondrial

physiology; release of cytochrome c; binding of cytochrome

c by Apaf-1 with concomitant activation of caspase-9;

amplification by the caspase cascade; cleavage of vital

cellular proteins; fission of cells into apoptotic bodies; and

finally disappearance of any traces of the cell when the

apoptotic bodies are engulfed by either neighbouring or

phagocytic cells.20

Heat shock proteins21 (HSPs) and other mediatorsin stress responsive signal transduction

The HSPs accumulate in cells exposed to heat and a variety

of other stressful stimuli. HSPs, which function mainly as

molecular chaperones, allow cells to adapt to gradual

changes and to survive in otherwise lethal conditions. HSPs

include antiapoptotic and proapoptotic proteins that

interact with a variety of cellular proteins. Their expression

level can determine the fate of the cell in response to a

death stimulus. The events of cell stress and cell death are

linked and HSPs induced in response to stress appear

to function at key regulatory points in the control of

apoptosis. The role of steryl-glucoside as a mediator in the

early stage of stress responsive signal transduction and

induction of HSP 70 has been also studied.22

Connective tissue repair processfollowing superficial mechanicaldermabrasion

There is no specific mechanism and cells, cytokines,

degradative enzymes, extra cellular matrix components -

all interact as the instruments in an orchestra to

progressively obtain connective tissue repair and a new

healthy epidermis. The fundamental processes induced are

at first fibroblast apoptosis under the wound and then

settlement by new fibroblasts drawn to and activated by

all the platelet and other cell synthesized growth factors.23

How can lasers stimulate fibroblasts?

Currently, laser fibroblast stimulation methods can be

separated into different groups: ablatives with cold

methods including standard Er:Yag laser and hot methods

including pulsed or scanned CO2 lasers and long pulse

Er:Yag and non ablatives with vascular or non vascular

effects.

After standard Er:Yag laser

There is no specific mechanism, as after a dermatome

induced wound.

After hot methods

Independent scarring processes are implemented with

immediate visualized shrinkage of the treated tissue.

These heat mediated events, although not fully known,

are complex, simultaneous and inextricably linked. The

most recent study found is on the effect of super pulsed

CO2 laser energy on keloid and normal dermal fibroblast.24

An in vitro model was used to determine the effect of super

pulsed CO2 laser energy (2.4, 4.7, 7.3 J/cm2) on normal

dermal and keloid-producing fibroblast proliferation and

release growth factors (bFGF, TGF-beta1 by sandwich

enzyme immunoassay) at four time points (0, 24, 72,

120 h). As seen above, bFGF is mitogenic but inhibits

collagen production, TGF-beta1 stimulates growth and

collagen secretion and is thought to be integral of keloid

formation. Measurements after application of super pulsed

CO2 demonstrated a trend toward increased bFGF

secretion in both fibroblast types; the increase was

significant in the keloid group at 4.7 J/cm2. A consistent

trend in suppression of TGF-beta1 was seen in both groups

exposed with the maximal effect occurring at 4.7 J/cm2.

Globally super pulsed CO2 enhances fibroblast replication

and seems to stimulate bFGF secretion and to inhibit

TGF-beta1 secretion. Close reading of the report shows

regional differences in growth rate secretion of bFGF and

TGF-beta1 and in response to super pulsed CO2 energy.

Because of the substantial post-treatment care and the

high incidence of side effects, research has been done to

find alternative methods to achieve the same laser fibro-

blast stimulation effects sparing the surface tissues. The

wavelength used must be preferentially absorbed by the

superficial dermis and weakly absorbed by melanin, and

the laser irradiation is often coupled with cryogen spray

or another cooling device to spare the epidermis.

With these lasers we are trying to create a dermal wound,

without epidermal damage.

Non-ablative vascular lasers or flash lamps(wavelengths: 500–650 nm/950 nm)

Non-ablative fibroblast stimulation is due to the action on

the micro-vessels. After laser induction of repairable

endothelial lesions, there is activation of the platelet and

probably mast-cell systems and all the previously described

cascade of scarring events (PDGF fibroblast activation,

protein syntheses, smooth muscle actin property acquisi-

tion) leading to final remodeling are initiated.

Non-ablative non vascular lasers (wavelengths: 805until 1540 nm)

The processes are less well understood but the heat shock

proteins (HSPs) seem to play the most important role in

the fibroblast stimulation.

Other modes of fibroblast stimulation

High molecular weight hyaluronic acid (HA)25

By interaction with other matrix proteins, HA provides

stability and elasticity to the extra cellular matrix. It has

been implicated in biological process such as cell adhesion,



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migration and proliferation. This study shows that high

molecular weight HA promotes the function of GJIC in

normal dermal fibroblasts by the production of growth

factors, FGF-2 and KGF.

Biological activity of trichloroacetic (TCA) andglycolic acids (GA)26

Beside their causticity, the biological mechanism by which

TCA and GA, two agents extensively used for chemical

peeling, might act remains unknown. The purpose of the

study was to examine in vitro the effect of TCA and GA

on human keratinocytes and the influence of the released

epithelial mediators on collagen and matrix MMPs

production by human dermal fibroblasts. After the acid

caustic application to the skin surface the products released

by the killed epithelial cells are resorbed and diffuse into

the dermis while the acids are neutralized by the body

fluids. TCA was cytotoxic (caustic necrosis) for keratino-

cytes at each tested pH and the conditioned keratinocyte

medium depressed protein and collagen synthesis and the

expression of MMPs when added to fibroblasts. The effect

of GA is very different, much gentler. It kills the epidermal

cells, by its caustic effect, at acid pH but does not modify

the biosynthetic or the remodeling capacities of fibroblasts

(no action on cell multiplication nor protein, collagen

or MMPs production). Other authors27,28 showed that GA,

at lower concentrations, exerts a stimulatory effect on

collagen production, but this was not confirmed in this

study.

Biological activity of phenols and sodium dodecylsulphate

The effects of resorcinol, phenol, 3, 5-xylenol, chlorox-

ylenol, and 4-hexyl-resorcinol were studied on normal

human epidermal keratinocytes and dermal fibroblasts for

cytotoxicity and cytokine release.29 This very complete and

scientific study has shown a structure-cytotoxicity relation-

ship for a series of phenols as well as an association of IL-1

alpha release with the cytotoxic effect. It demonstrated

a cytokine cascade amplification step by the actions of

stimulated keratinocyte media on cultured dermal fibro-

blasts, identifying IL-1 alpha as the principal initiator of

chemokine synthesis.

Selective up regulation by retinoic acid

Retinoic acid has recently been shown to increase the

expression of Fas-ligand molecule by fibroblasts.30

Age-related response to L-ascorbic acid31

At a concentration of 0.15mM, L-ascorbic acid (AA)

allows maximal fibroblast stimulation with an increase

in collagen secretion, but to a lower extent for type III

compared to type I, leading to an increase in the type I/III

collagen ratio. This stimulation decreases in a statistically

significant linear manner with donor age, especially for the

secretion of type I collagen. Moreover, analysis of AA

stimulation as a function of body site showed that during

aging, the loss of AA stimulation of type I and III collagen

synthesis was more for per auricular than for mammary

skin. This led the investigators to consider that UV-exposed

cutaneous sites may accelerate cellular dermal aging in

terms of response to AA.

Conclusion

A minimal knowledge of all these complex and intricate

phenomena is required for clinicians to analyse literature

accurately and objectively. Facing a study with cytokine

rate measurements raises the question: have the authors

chosen the correct factors or combination of factors? An

additional difficulty is to understand that none of these

growth factors act in isolation and even if a study is able to

characterize some of the more important growth factors,

other families always exist and play important and often

controversial roles.

The main goal of this report is not so much to elicit

fibroblast network but to highlight the exceptionally

complex pattern of specific interactions and effects of the

dermal integrity and homeostasis regulation systems:

1. Different cytokines and growth factors, their varied

forms (latent/active), receptors or inhibitors and also

their mRNA transcription and transduction signals.

2. Diverse enzymes and inhibitor enzymes, such as

metalloproteinases.

3. Heat shock protein balance and their relationships with

TNF and Fas-ligand receptors.

Deciphering the essential and complex role of fibroblast

environment is an ongoing process and will provide

opportunities to explore pathways to inhibit or enhance

appropriate cytokines in order to control cell senescence

and wound or pathological healing. For a clinician,

however, full comprehension of all these phenomena is

not yet in place – despite rapid progress it will still be some

time before we have a full understanding by cellular biology

of how lasers, flash lamps, peels, mechanical derma-

brasions, fillers or topicals work.

References

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edn. Oxford: Blackwell, 1998.2. Cavaillon JM. Les cytokines. 2nd edition. Masson, 1996.

3. Watson D, Keller GS, Lacombe V, et al. Autologousfibroblasts for treatment of facial rhytids and dermaldepressions. A pilot study. Arch Facial Plast Surg 1999; 1:165–70.



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fibroblasts: what's new in cellular biology?

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