Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease

Kramann, Rafael; DiRocco, Derek P.; Humphreys, Benjamin D.

doi:10.1002/path.4253

Cited by 190 publications

(179 citation statements)

References 195 publications

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“…20,42 It is not yet clear whether these progenitors are resident fibroblasts, pericytes, or as-yet-undefined subsets of these cells, as recently reviewed. 43 The searchable dataset that accompanies this paper should provide a substantial source of novel gene markers that might help further define various interstitial stromal cell subsets in kidney. Our validation of the TRAP dataset identified many genes that may play important roles in regulating myofibroblast biology during fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

Grgic

Krautzberger

Hofmeister

et al. 2014

Journal of the American Society of Nephrology

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Myofibroblasts secrete matrix during chronic injury, and their ablation ameliorates fibrosis. Development of new biomarkers and therapies for CKD will be aided by a detailed analysis of myofibroblast gene expression during the early stages of fibrosis. However, dissociating myofibroblasts from fibrotic kidney is challenging. We therefore adapted translational ribosome affinity purification (TRAP) to isolate and profile mRNA from myofibroblasts and their precursors during kidney fibrosis. We generated and characterized a transgenic mouse expressing an enhanced green fluorescent protein (eGFP)-tagged L10a ribosomal subunit protein under control of the collagen1a1 promoter. We developed a one-step procedure for isolation of polysomal RNA from collagen1a1-eGFPL10a mice subject to unilateral ureteral obstruction and analyzed and validated the resulting transcriptional profiles. Pathway analysis revealed strong gene signatures for cell proliferation, migration, and shape change. Numerous novel genes and candidate biomarkers were upregulated during fibrosis, specifically in myofibroblasts, and we validated these results by quantitative PCR, in situ, and Western blot analysis. This study provides a comprehensive analysis of early myofibroblast gene expression during kidney fibrosis and introduces a new technique for cell-specific polysomal mRNA isolation in kidney injury models that is suited for RNA-sequencing technologies.

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Section: Discussionmentioning

confidence: 99%

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

Grgic

Krautzberger

Hofmeister

et al. 2014

Journal of the American Society of Nephrology

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“…Myofibroblasts are currently a potent target for developing antifibrotic therapies (48). Our findings provide insights to help identify potentially specific pathways.…”

Section: 35)mentioning

confidence: 99%

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

Kim

Barron²,

Martin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

127

126

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Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate-derived mesenchymal stem cells (MSCs) and the TGF-β1-regulated pathways that modulate MSC proliferation and myofibroblast differentiation. Human prostate MSCs combined with prostate cancer cells expressing TGF-β1 resulted in commitment to myofibroblasts. TGF-β1-regulated runt-related transcription factor 1 (RUNX1) was required for cell cycle progression and proliferation of progenitors. RUNX1 also inhibited, yet did not block, differentiation. Knockdown of RUNX1 in prostate or bone marrow-derived MSCs resulted in cell cycle arrest, attenuated proliferation, and constitutive differentiation to myofibroblasts. These data show that RUNX1 is a key transcription factor for MSC proliferation and cell fate commitment in myofibroblast differentiation. This work also shows that the normal human prostate gland contains tissue-derived MSCs that exhibit multilineage differentiation similar to bone marrow-derived MSCs. Targeting RUNX1 pathways may represent a therapeutic approach to affect myofibroblast proliferation and biology in multiple disease states. myofibroblast | MSC | RUNX1 | TGF-β1 | reactive stroma

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“…PDGF, mainly produced by Kupffer cells, is the predominant mitogen for activated HSCs that stimulates their proliferation, while TGF-β is considered the most important cytokine that stimulates HSCs to fi brogenesis [19,44,46].…”

Section: Activation Of Mfsmentioning

confidence: 99%

“…Initiation refers to early changes in gene expression and phenotype that render the cells responsive to other cytokines and stimuli. Initiation results mostly from paracrine stimulation, primarily due to changes in the surrounding extracellular matrix, as well as exposure to lipid peroxides and products of damaged hepatocytes [19,[43][44][45]. Perpetuation results from the effects of these stimuli on maintaining the activated phenotype and generating fi brosis.…”

Section: Activation Of Mfsmentioning

confidence: 99%

Myofibroblasts in Normal and Fibrotic Liver in Different Animal Species

Kukolj

2014

Acta Veterinaria

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Myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells, may have a very heterogeneous origin. The myofibroblasts may be derived from a variety of sources including resident mesenchymal cells, epithelial to mesenchymal transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells, or derived from bone marrow precursors. In normal conditions, fibroblastic cells exhibit a low extracellular matrix production ability. After tissue injury, they become activated by cytokines locally released from inflammatory and resident cells to migrate into the damaged tissue and to synthesize extracellular matrix components. The investigation of cytoskeletal and cell surface markers showed a certain degree of heterogeneity of these cells. The reason for this is that markers these cells express to a large extent depend on the type of animal, age and stage of development of fibrosis. A better knowledge of the molecular mechanisms involved in the appearance of differentiated myofibroblasts in different pathological situations will be useful for understanding the development of fibrosis, its prevention and therapy

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Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease

Cited by 190 publications

References 195 publications

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

Translational Profiles of Medullary Myofibroblasts during Kidney Fibrosis

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

Myofibroblasts in Normal and Fibrotic Liver in Different Animal Species

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