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patients. Additionally, from the practical point of view, several genetically-altered
mice are commonly available on a C57/BL6 background representing a mouse
strain that is generally less susceptible to brogenesis.
For investigation of the role of T cells in the context of IBD related brogenesis,
the T cell transfer model appears to be promising. With regard to infection-induced
models of brosis one should consider the difculty to distinguish between the
impact of the applied pathogens as a pro-brotic driver and the commensal microbiota of the animals. Moreover, Salmonella typhi, the commonly used bacterial species to induce experimental brosis has not been shown to be associated with the
pathogenesis of human IBD.
With regard to the heterotopic intestinal transplant model, the rather articial
approach may be a signicant limitation of this model and the immune response
towards intestinal resections may be slightly different depending on the individual
mouse strain used. Furthermore, the speed of brosis development as well as the
absence of vasculature indicate signicant differences compared to the pathophysiology of brosis in human IBD patients.
The SAMP1/Yit mouse model possesses particularly high relevance to human
brostenotic IBD given the ileal disease localization and appearance of stricture
development as well as the absence of an external stimulus. However, the hampered
availability of these animals limits a broader use of this promising model.
The gut microbiota-induced model bears the advantage of direct dependence on
bacteria-derived components and may therefore be particularly appropriate to study
the impact of microbiota on brosis development. Finally, postoperative models
using anastomotic brosis imply a high relevance to human brostenotic CD since
the same surgical approach is used as in human patients and may therefore allow to
study the outcome of routine bowel resection.
In summary, available murine models of intestinal brosis are valuable tools to
gather relevant information for human IBD patients with stricturing disease.
Independent on the model used, as brosis is primarly a consequence of chronic
inammation, differentiation of anti-inammatory from anti-brotic treatment
effects should be considered.
9.3 Sources ofMesenchymal Cells inIntestinal Fibrosis
Mesenchymal cells are key effector cells in brogenesis and can present as smooth
muscle cells, broblast and myobroblasts [66]. The latter, myobroblasts, respresent an activated or differentiated form of broblasts [67]. While broblasts are resident in the interstitium of all human tissues and organs, a persistent stimulus such
as injury or inammation results in broblast activation (also referred to as diseaseactivated myobroblasts) [68]. In addition, activation can be facilitated by various
autocrine and paracrine signals as well as by microbiota- or damage-associated
molecular patterns and ligation of other pattern recognition receptors [38, 69]. As a
9 Animal Models andSources ofMesenchymal Cells inIntestinal Fibrosis
135
consequence, broblasts become susceptible to inammatory stiumulation due to
an increased expression of receptors for pro-inammatory cytokines including
TNF-α [70]. Upon inammation-mediated activation, myobroblasts proliferate
and produce various molecules that contribute to both, the perpetuation of local
inammation as well as to ECM protein deposition [32]. Over recent years, different sources of myobroblasts have been identied that will be described in the
following.
One key aspect of intestinal brogenesis is the proliferation of broblasts.
Interestingly, it was demonstrated that broblast proliferation rates per se are
increased in human CD and UC patients as compared to broblasts from healthy
control patients [71]. Furthermore, is was shown, that various growth factors
(known to be increased in the inamed gut) including insulin-like growth factor I
(IGF-I), basic broblast growth factor (bFGF), epithelial growth factor (EGF),
connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF) as
well as pro- inammatory cytokines such as IL-1β, IL-6 and TNF-α result in
enhanced broblast proliferation in vitro [71–73]. Transforming growth factor
(TGF)-β1 can further fuel broblast proliferation, however, not by direct stimulation of proliferation rates but by enhancing PDGF receptor, CTGF and IGF-1
synthesis [40]. Finally, direct interaction between broblasts and different cell
types including mast cells, eosinophils or T cells can further foster broblast
proliferation [74].
Within the inamed gut, a chemotactic gradient triggers the active inux of various cells including broblasts that can most likely migrate from all layers of the
intestinal wall as long as the gradient persists. The extent of broblast migration
largely dependents on the duration and severity of the underlying inammation.
Among various soluble factors that stimulate broblast migration, bronectins
appears to be the most potent one [75, 76]. In addition to bronectin, other paracrine
and endocrine pathways to stimulate intestinal broblast migration have been identied [77]. Finally, invitro experiments with (human CD) broblasts indicate an
reduced migration of these cells after pro-inammatory stimulation with TNF-α and
IFN-γ; an effect that may help to maintain these broblasts in situ during brosis
development [77].
Mesencyhmal stellate cells are characterized by a low mitogenic activity and their
involvement in the retinoic acid metabolism. These cells are known to be crucially
involved in liver brosis [78] and differentiate into broblasts and mediate ECM
accumulation [79]. Interestingly, cells with retinoid-rich lipid droplets and a stellatelike morphology have also been identied within the submucosal layer [80]. Stellate
cells isolated from human IBD patients differentiate into broblasts much faster
(reected by an accelerated α-SMA acquisition), proliferate faster and secrete
enhanced amounts of ECM components than cells from healthy control patients [81].
It is well-known that adult bone marrow stem cells can differentiate into various
adult lineages including broblasts [82]. Indeed, the ability of bone-marrow-derived
cells to engraft in damaged tissue is increased and these cells were found to transdifferentiale into intestinal pericryptal broblasts in humans and animals [83]. Notably,
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a substantial amount of myobroblasts may be derived from the bone marrow as
elegantly shown in IL-10-decient mice [84].
Furthemore, in the experimental TNBS-induced model of colitis, transplanted
bone marrow cells were found to increase with disease severity and contributed to
recovery from inammation through differentiation into activated broblasts [85].
Similarly, tissue repair following previous DSS challenge can be accelerated by
intravenous administration of immortalized stem cells and does not require prior
ablation of the immune system [86].
There is compelling evidence that in addition to the above-mentioned classical
sources of broblasts, more recently identied mechanisms are also crucially
involved in intestinal brogenesis. For example, epithelial-to-mesenchymal transi-
tion (EMT) results in a signicant alteration of the epithelial cell phenotype and
function towards that of mesenchymal cells [87]. While TGF-β1 represents the
strongest inducer of EMT, IGF-1 and -2, EGF, FGF-2 as well as TNF-α, bronectins, brin and reactive oxygen species can further inuence this process [87, 88].
As a consequence, affected cells do not longer express epithelial markers such as
E-cadherin, catenins and cytokeratins but constitute a spindle shape morphology
and synthesize characteristic broblast proteins such as broblast-specic protein
(FSP)-1, α-SMA, vimentin and secrete collagens and bronectin [87, 89].
Furthermore, these cells display an altered capacity of migration as well as inltration and show an increased resistence to apoptosis while the mitosis rate is reduced
[87]. EMT has been detected in renal, pulmonary and liver brosis and the overall
impact of EMT on brogenesis may be signicant since up to 30% of broblast in
renal brosis are assumed to be EMT derived [90]. By now, there is no direct proof
for EMT in human brostenotic IBD patients, however, EMT was demonstrated in
experimental intestinal inammation with a change of epithelial cell function
towards the production of collagen [91]. Furthermore, given the increasing evidence of EMT in brotic organs other than the gut, it is highly suggestive that
EMT represents a general feature of organ brosis also being present in intestinal
brosis [92].
Similarly to epithelial cells, endothelial cells are able to transform into mesenchymal cells (also referred to as endothelial-to-mesenchymal-transition (EndoMT)).
For example, it was reported that embroyogenic stem cells that differentiate into
endothelial cells may change their phenotype towards a mesenchymal differentiation such as smooth muscle cells (SMC) [93]. Additionally, adult endothelial cells
of the bovine aortic or pulmonary artery origin were shown to maintain their ability
to transdifferentiate into SMCs [94]. In the context of wound healing experiments,
microvascular endothelial cells were found to transdifferentiate into spindle-shaped
mesenchymal cells under persistent inammatory conditions. For experimental cardiac brosis, it was estimated that endothelial cells represent one-third of the total
pool of tissue-inltrating broblasts [95]. Several similarities between EMT and
EndoMT have been reported: TGF-β1 is known to be a potent driver of EndoMT as
well, while Insulin-like-growth factor-II and pro-inammatory cytokines such as
9 Animal Models andSources ofMesenchymal Cells inIntestinal Fibrosis
137
IL-1β and TNF-α are able to foster EndoMT transdifferentiation [96]. EndoMT has
recently been demonstrated in colonic brosis of TNBS-treated mice and in
microvessels of the IBD mucosa [97]. Therefore, in line with the evidence of several
key inducers of EndoMT within the gut, it is most likely that EndoMT is involved
in intestinal brogenesis as well [97].
Vascular smooth muscle cells (vSMC) encompasses arteries and veins while
capillaries are surrounded by single cells called pericytes [98]. Both cell types
comprise similar cytoskeletal components such as α-SMA and desmin and are
located between the endothelium and the interstitium. Pericytes regulate various
functions during inammation and also mediate ECM degradation [99]. It has been
demonstated that pericytes can be considered as an additional source for broblasts
during tissue repair. In addition, pericytes were reported be involed in inammationassociated tissue brosis as these cells can detach from vessels and differentiate into
a collagen type-I-producing broblast-like cell [100]. This observation may explain
why increased levels of ECM deposition during the initial phase of brogenesis
accumulate around blood vessels.
By now, there are only a very few reports on the involvement of pericytes in
intestinal brogenesis, which may be at least partially explained by the lack of
appropriate invitro models. In the TNBS-induced colitis model, it was shown that
vSMCs as well as pericytes can be successfully collected from the bone marrow of
mice [85]. Hower the exact role of these cells during intestinal brosis is still
unknown.
Fibrocytes represent bone marrow-derived circulating mesenchymal cells
expressing hematopoietic and mesenchymal markers such as CD34 (stem cell
marker), CD45 (leukocyte antigen) and CD14 (monocytic marker) [101]. In addition, brocytes secrete typical broblast components such as collagens and α-SMA
as well as ECM-modifying enzymes. Fibrocytes were furthermore shown to be able
to differentiate into broblasts invitro and invivo [102].
Under inammatory conditions, brocytes leave the bone marrow and move
directly towards the site of inammation in a CCR2-dependent pathway.
Subsequently, broblasts can transdifferentiate into several cell types including epithelial, endothelial, neuronal cells and mesenchymal cells [103]. Fibrocytes are
characterized by the expression of CD90 and the absence of CD34 and CD45
expression as well as monocyte markers. In contrast, cells expressing CD34 and
CD45 or myeloid antigens (e.g. CD11b and CD13), and owing the ability to synthesize collagen are dened as brocytes and differ from resident leukocytes, dendritic
cells, endothelial cells and tissue resident broblasts [101].
Fibrocytes have been identied as an important driver of tissue brosis in experimental models of pulmonary, cardiac, renal and vascular brosis [104–106].
Uniformely, brocyte inhibition resulted in a decreased amount of myobroblasts
and collagen synthesis. In addition to experimental data, brocytes have been identied in several human diseases including scars and keloids, asthma, nephrogenic
brosis, systemic sclerosis, atherosclerosis, chronic pancreatitis, chronic cystitis,
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D. Bettenworth
and tumor-associated stromal reaction [107–109]. Given the fact that all these disorders are associated with persistent inammatory inltrates, it is most likely that
brocytes are also involved in intestinal brosis as well.
In face of the various above-mentioned sources of mesenchymal cells and their
dynamic role in intestinal brogenesis, it is crucial to track the cellular fate in experimental settings to eludicate the cellular origin and function in vivo. Traditional
histological evaluation of the intestine usually requires the death of the animal and
therefore does not allow a longitudinal evaluation. Genetically-engineered mice
represent a promising tool to study mesenchymal cell fate. For example, α-SMA-
+
GFP mice were used to visualize α-SMA
cells in a recently established α-SMA
promotor driven cre-loxP mediated expression of yellow uorescent protein mice
(aSMACre;YFP
f/f
mice) [110]. In the context of renal brosis, the specic function
of proliferating myobroblasts was nicely studied by of the use of mice in which the
viral thymidine kinase was expressed under the control of the α-SMA promotor
[110]. In addition, the impact of pericytes was successfully studied by using mice in
which yellow and red uorescent protein, respectively, were expressed under the
control of Cspg4 and Pdgfrb genes—both being fairly specic pericyte markers
[110, 111]. Finally, the role of EMT was addressed by using transgenic reporter
mice using γGT-Cre [110].
In addition to genetic modications, it was shown recently that non-invasive
MRI may be helpful to assess the fate of mesenchymal stem cells [112, 113]. For
example, Kraitchman and collegues demonstrated that the role of magneticallylabelled mesenchymal stem cells (MCSs) in cardiac brosis can be evaluated using
an 1.5T MRI scanner [113]. However, recent work by Chen etal. indicated that
assessment of iron-oxide labeled MCSs can be confounded by iron-oxide particles
that were ingested by macrophages [114]. With regards to the intestine, recently a
novel approach to evaluate the fate of implanted mesenchymal cells was introduced
employing cell sheets. Here, magnetically and uorescently labeled bone-marrow
derived mesenchymal cells were applied to a cell sheet and administered to a murine
stula model. Subsequently, cellular fate was successfully monitored invivo by a
4.7T MRI and confocal laser endomicroscopy [115].
9.4 Conclusions
The pathophysiological understanding of intestinal brogenesis has signicanyly
increased over recent years. Multiple animal models are available to test novel antibrotic compounds. Beside classical sources such as broblast proliferation and
migration, several other sources of mesenchymal cells have been identied including stem cells, EMT, EndoMT and pericytes. Further studies evaluating the fate and
specic contributions of these cell types to brotic alterations are warranted and
may pave the way to a targeted therapeutic manipulation to stop or ameliorate intestinal brosis (Fig.9.1).
derived stem cells
9 Animal Models andSources ofMesenchymal Cells inIntestinal Fibrosis
Epithelial cells
EMT
139
Myofibroblast
Myofibroblast
Fibroblast
EndoMT
Bone marrow
Muscle cell
Immune cell
Endothelial cells
Fig. 9.1 Sources of broblasts in intestinal brogenesis. In addition, to proliferation and migration, broblasts can derive from precursors such as intestinal stellate cells and brocytes or via
epithelial- or endothelial-to-mesenchymal transition (EMT, EndoMT). Additionally, broblasts
can generate form circulating brocytes or from bone marrow stem cells. By now, the role of pericytes in intestinal stricture formation is unclear
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