The myofibroblast matrix: implications for tissue repair and fibrosis

Klingberg, Franco; Hinz, Boris; White, Eric S.

doi:10.1002/path.4104

Cited by 640 publications

(510 citation statements)

References 225 publications

(275 reference statements)

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“…Myofibroblasts are responsible for the synthesis of large amounts of ECM 1, 2, 3, 4, 28. Here, we show that ACHP is able to completely abrogate the TGFβ1‐induced differentiation of both dermal and lung fibroblasts into myofibroblasts, as revealed by the inhibition of the formation of the stress fibre components αSMA and SM22α.…”

Section: Discussionmentioning

confidence: 60%

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The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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Excessive accumulation of a collagen‐rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGFβ1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF‐κB) pathway by phosphorylating IκB with the enzyme IκB kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2‐Amino‐6‐[2‐(cyclopropylmethoxy)‐6‐hydroxyphenyl]‐4‐(4‐piperidinyl)‐3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF‐κB pathway. It is not known whether ACHP has potential anti‐fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGFβ1‐induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha‐smooth muscle actin (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post‐treatment with ACHP partly reversed the expression of αSMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen‐modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF‐κB pathway plays an important role in myofibroblast biology.

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Section: Discussionmentioning

confidence: 60%

“…Aberrant expression of FN1 under the influence of TGFβ1 contributes to fibrosis 2. Therefore, we have examined whether ACHP is able to prevent the TGFβ1‐induced production of fibronectin.…”

Section: Resultsmentioning

confidence: 99%

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Mia

Bank

2015

J Cellular Molecular Medi

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“…This theory is corroborated by a recent immunohistochemical study on B. besnoiti cysts, suggesting myofibroblasts as host cells during cyst stage of B. besnoiti, 14 since myofibroblasts are capable of producing both abundant ECM elements and different types of collagen, including collagen type I. 27,33 The distribution of tissue cysts within the skin and within the whole body is striking. In skin, cysts are more frequently observed in the papillary layer than in the reticular layer.…”

mentioning

confidence: 64%

Naturally Acquired Bovine Besnoitiosis

Langenmayer¹,

Gollnick²,

Majzoub-Altweck³

et al. 2014

Vet Pathol

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The pathogenesis of bovine besnoitiosis, a disease of increasing concern within Europe, is still incompletely understood. In this study, disease progression after natural infection with the causative apicomplexan Besnoitia besnoiti was monitored in histological skin sections of 5 individual female cattle over time. High-frequency skin sampling of 2 cattle with mild and 2 with severe acute, subacute, and chronic besnoitiosis, as well as from 1 animal during subclinical disease, enabled documentation from the beginning of the disease. Skin sections were stained with hematoxylin and eosin and Giemsa, periodic acid-Schiff reaction, and anti-Besnoitia immunohistochemistry. In all 4 clinically affected animals, tachyzoite-like endozoites could be detected for the first time by immunohistochemistry, and tissue cyst evolution was monitored. Besnoitiosis-associated lesions were not detected in the animal showing the subclinical course. Because of the inconsistency of the nomenclature of Besnoitia tissue cyst layers in the literature, a new nomenclature for B. besnoiti cyst wall layers is proposed: tissue cysts consist of a hypertrophied host cell with enlarged nuclei, an intracytoplasmic parasitophorous vacuole with bradyzoites, a sometimes vacuolated inner cyst wall, and an outer cyst wall in more developed cysts. Inner and outer cyst walls can be readily distinguished by using special stains. In 1 animal, extracystic B. besnoiti zoites were immunohistochemically detected during the chronic stage. At necropsy, the 2 severely affected cows displayed large numbers of B. besnoiti cysts in a variety of tissues, including the corium of the claws, contributing mainly to the development of chronic laminitis in these 2 cases.

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“…Endothelial cells are able to form tubular vessel-like structures when embedded as spheroids in a three-dimensional collagen gel (Korff R Walser et al Vascularisation of co-culture spheroids et al, 2001). Finally, NHDF are an important source of proteins of the extracellular matrix (Klingberg et al, 2013), and, therefore, contribute to the stabilisation of newly formed microvessels (Nicosia et al, 2011). The vascularisation of the generated spheroids was analysed in the mouse dorsal skinfold chamber model.…”

Section: Introductionmentioning

confidence: 99%

Generation of co-culture spheroids as vascularisation units for bone tissue engineering

Walser

Metzger²,

Görg³

et al. 2013

eCM

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Cell spheroids represent attractive building units for bone tissue engineering, because they provide a threedimensional environment with intensive direct cellcell contacts. Moreover, they allow for co-culture of both osteoblasts and vessel-forming cells, which may markedly increase their survival and vascularisation after transplantation. To test this hypothesis, we generated coculture spheroids by aggregating different combinations of primary human osteoblasts (HOB), human dermal microvascular endothelial cells (HDMEC) and normal human dermal fibroblasts (NHDF) using the liquid overlay technique. Mono-culture spheroids consisting either of HOB or HDMEC served as controls. After in vitro characterisation, the different spheroids were transplanted into dorsal skinfold chambers of CD1 nu/nu mice to study in vivo their viability and vascularisation over a 2-week observation period by means of repetitive intravital fluorescence microscopy and immunohistochemistry. In vitro, co-culture spheroids containing HDMEC rapidly formed dense tubular vessel-like networks within 72 h and exhibited a significantly decreased rate of apoptotic cell death when compared to mono-culture HDMEC spheroids. After transplantation, these networks interconnected to the host microvasculature by external inosculation. Of interest, this process was most pronounced in HOB-HDMEC spheroids and could not further be improved by the addition of NHDF. Accordingly, HOB-HDMEC spheroids were larger when compared to the other spheroid types. These findings indicate that HOB-HDMEC spheroids exhibit excellent properties to preserve viability and to promote proliferation and vascularisation. Therefore, they may be used as functional vascularisation units in bone tissue engineering for the seeding of scaffolds or for the vitalisation of non-healing large bone defects.

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The myofibroblast matrix: implications for tissue repair and fibrosis

Cited by 640 publications

References 225 publications

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

The IκB kinase inhibitor ACHP strongly attenuates TGFβ1‐induced myofibroblast formation and collagen synthesis

Naturally Acquired Bovine Besnoitiosis

Generation of co-culture spheroids as vascularisation units for bone tissue engineering

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