Role of mesenchymal fibro/adipogenic progenitors in homeostasis and disease : from signaling to fibrosis
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Date
2019
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Abstract
Fibrosis, the dysregulated accumulation of connective tissue (CT), is a hallmark of
multiple pathologies where inflammation is not fully resolved. The main components of
the CT are the extracellular matrix (ECM) and its tissue-resident mesenchymal stromal
cells (MSCs), which actively produce and remodel ECM during development,
homeostasis, and disease. Fibrosis and/or fibro-fatty replacement of the functional tissue
is a common feature of Duchenne Muscular Dystrophy (DMD), but it is also observed in
neuromuscular diseases. It is generally accepted that these mesenchymal progenitor cells
(MPCs) [hereafter referred to as fibro/adipogenic progenitors (FAPs)] are the progenitors
of pathological myofibroblasts and adipocytes during muscular dystrophy and chronic
muscle damage, but also important players for proper tissue regeneration. Their
dysregulated activity during pathology impairs proper tissue repair. Our overall hypothesis
is that efficient regeneration depends on a complex network of signaling interactions
between multiple cell types leading to the proper coordination of their function.
The best-known marker for FAPs is the receptor tyrosine kinase (RTK) plateletderived growth factor receptor alpha (PDGFRa). Several attempts to block the
dysregulated RTK activity of PDGFRa in pathology have been successfully done,
therefore, PDGFRa signaling emerges as a potential target against fibrosis. TGF-bmediated signaling pathways are commonly accepted to be fibrotic, to induce the
proliferation of FAPs and myofibroblast differentiation from these precursors. TGF-b
signaling and its ligands are augmented during DMD, and fibrosis in several tissues.
Hence, TGF-b is a known driver of the fibrotic process. Here, we investigated the role of
TGF-b signaling on PDGFRa expression and signaling, along with studying a functional
cross-talk between PDGFRa and TGF-b in FAPs and MPCs.
Canonical Wnt Tcf/Lef transcription factors are important players during
development and controlling stem cell fate. Recently, the canonical Wnt signaling cascade
emerged as a new system to study fibrosis in several tissues. Importantly, the role of
Tcf/lef proteins in MPCs has not been studied yet. Additionally, whether TGF-b has an
impact on Wnt signaling and/or may crosstalk through the regulation of these Wnt
transcription factors has not been explored yet.
In the present Ph.D. thesis, we focused on the TGF-b signaling pathway and its
role in FAPs and MPCs. The main findings are; 1. MPCs are present in skeletal muscle
under normal conditions and are increased in several models where muscle fibrosis and
TGF-b are a hallmark. These Tcf7l2+ progenitors lie near macrophages mainly
concentrated in dystrophic necrotic-regenerating foci. 2. We suggest that the historically
named muscle CT fibroblasts isolated via pre-plating correspond to a phenotypically and
biochemically FAPs-like population of adherent MPCs. These adherent cells respond in
the same fashion to TGF-b signaling and the tyrosine kinase inhibitor Nilotinib as FAPs.
3. The role and/or cross-talk of TGF-b signaling in the regulation of PDGFRa expression
and signaling in mesenchymal progenitors is described: i) PDGFRa expression is strongly
reduced by TGF-b signaling in FAPs, Hic1+ MPs, skin fibroblasts, and two different MPs
cell lines. ii) PDGFRa-mediated gene expression is altered during muscle regeneration in
FAPs and after TGF-b1 treatment. iii) Pharmacological inhibition of PDGFRa impaired the
TGF-b-mediated ECM remodeling and blocked the TGF-b1-induced migration of MPs. 4.
the ubiquitin-proteasome system (UPS). Via Tcf7l2 pharmacological inhibition we suggest
that Tcf7l2 plays a role in regulating FAPs survival and fate.
Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and
signaling governing pathways might be suitable for a novel therapeutic target for the
treatment of MD, neurodegenerative diseases, non-malignant fibroproliferative disorders,
and aging.Fibrosis, the dysregulated accumulation of connective tissue (CT), is a hallmark of
multiple pathologies where inflammation is not fully resolved. The main components of
the CT are the extracellular matrix (ECM) and its tissue-resident mesenchymal stromal
cells (MSCs), which actively produce and remodel ECM during development,
homeostasis, and disease. Fibrosis and/or fibro-fatty replacement of the functional tissue
is a common feature of Duchenne Muscular Dystrophy (DMD), but it is also observed in
neuromuscular diseases. It is generally accepted that these mesenchymal progenitor cells
(MPCs) [hereafter referred to as fibro/adipogenic progenitors (FAPs)] are the progenitors
of pathological myofibroblasts and adipocytes during muscular dystrophy and chronic
muscle damage, but also important players for proper tissue regeneration. Their
dysregulated activity during pathology impairs proper tissue repair. Our overall hypothesis
is that efficient regeneration depends on a complex network of signaling interactions
between multiple cell types leading to the proper coordination of their function.
The best-known marker for FAPs is the receptor tyrosine kinase (RTK) plateletderived growth factor receptor alpha (PDGFRa). Several attempts to block the
dysregulated RTK activity of PDGFRa in pathology have been successfully done,
therefore, PDGFRa signaling emerges as a potential target against fibrosis. TGF-bmediated signaling pathways are commonly accepted to be fibrotic, to induce the
proliferation of FAPs and myofibroblast differentiation from these precursors. TGF-b
signaling and its ligands are augmented during DMD, and fibrosis in several tissues.
Hence, TGF-b is a known driver of the fibrotic process. Here, we investigated the role of
TGF-b signaling on PDGFRa expression and signaling, along with studying a functional
cross-talk between PDGFRa and TGF-b in FAPs and MPCs.
Canonical Wnt Tcf/Lef transcription factors are important players during
development and controlling stem cell fate. Recently, the canonical Wnt signaling cascade
emerged as a new system to study fibrosis in several tissues. Importantly, the role of
Tcf/lef proteins in MPCs has not been studied yet. Additionally, whether TGF-b has an
impact on Wnt signaling and/or may crosstalk through the regulation of these Wnt
transcription factors has not been explored yet.
In the present Ph.D. thesis, we focused on the TGF-b signaling pathway and its
role in FAPs and MPCs. The main findings are; 1. MPCs are present in skeletal muscle
under normal conditions and are increased in several models where muscle fibrosis and
TGF-b are a hallmark. These Tcf7l2+ progenitors lie near macrophages mainly
concentrated in dystrophic necrotic-regenerating foci. 2. We suggest that the historically
named muscle CT fibroblasts isolated via pre-plating correspond to a phenotypically and
biochemically FAPs-like population of adherent MPCs. These adherent cells respond in
the same fashion to TGF-b signaling and the tyrosine kinase inhibitor Nilotinib as FAPs.
3. The role and/or cross-talk of TGF-b signaling in the regulation of PDGFRa expression
and signaling in mesenchymal progenitors is described: i) PDGFRa expression is strongly
reduced by TGF-b signaling in FAPs, Hic1+ MPs, skin fibroblasts, and two different MPs
cell lines. ii) PDGFRa-mediated gene expression is altered during muscle regeneration in
FAPs and after TGF-b1 treatment. iii) Pharmacological inhibition of PDGFRa impaired the
TGF-b-mediated ECM remodeling and blocked the TGF-b1-induced migration of MPs. 4.
the ubiquitin-proteasome system (UPS). Via Tcf7l2 pharmacological inhibition we suggest
that Tcf7l2 plays a role in regulating FAPs survival and fate.
Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and
signaling governing pathways might be suitable for a novel therapeutic target for the
treatment of MD, neurodegenerative diseases, non-malignant fibroproliferative disorders,
and aging.Fibrosis, the dysregulated accumulation of connective tissue (CT), is a hallmark of
multiple pathologies where inflammation is not fully resolved. The main components of
the CT are the extracellular matrix (ECM) and its tissue-resident mesenchymal stromal
cells (MSCs), which actively produce and remodel ECM during development,
homeostasis, and disease. Fibrosis and/or fibro-fatty replacement of the functional tissue
is a common feature of Duchenne Muscular Dystrophy (DMD), but it is also observed in
neuromuscular diseases. It is generally accepted that these mesenchymal progenitor cells
(MPCs) [hereafter referred to as fibro/adipogenic progenitors (FAPs)] are the progenitors
of pathological myofibroblasts and adipocytes during muscular dystrophy and chronic
muscle damage, but also important players for proper tissue regeneration. Their
dysregulated activity during pathology impairs proper tissue repair. Our overall hypothesis
is that efficient regeneration depends on a complex network of signaling interactions
between multiple cell types leading to the proper coordination of their function.
The best-known marker for FAPs is the receptor tyrosine kinase (RTK) plateletderived growth factor receptor alpha (PDGFRa). Several attempts to block the
dysregulated RTK activity of PDGFRa in pathology have been successfully done,
therefore, PDGFRa signaling emerges as a potential target against fibrosis. TGF-bmediated signaling pathways are commonly accepted to be fibrotic, to induce the
proliferation of FAPs and myofibroblast differentiation from these precursors. TGF-b
signaling and its ligands are augmented during DMD, and fibrosis in several tissues.
Hence, TGF-b is a known driver of the fibrotic process. Here, we investigated the role of
TGF-b signaling on PDGFRa expression and signaling, along with studying a functional
cross-talk between PDGFRa and TGF-b in FAPs and MPCs.
Canonical Wnt Tcf/Lef transcription factors are important players during
development and controlling stem cell fate. Recently, the canonical Wnt signaling cascade
emerged as a new system to study fibrosis in several tissues. Importantly, the role of
Tcf/lef proteins in MPCs has not been studied yet. Additionally, whether TGF-b has an
impact on Wnt signaling and/or may crosstalk through the regulation of these Wnt
transcription factors has not been explored yet.
In the present Ph.D. thesis, we focused on the TGF-b signaling pathway and its
role in FAPs and MPCs. The main findings are; 1. MPCs are present in skeletal muscle
under normal conditions and are increased in several models where muscle fibrosis and
TGF-b are a hallmark. These Tcf7l2+ progenitors lie near macrophages mainly
concentrated in dystrophic necrotic-regenerating foci. 2. We suggest that the historically
named muscle CT fibroblasts isolated via pre-plating correspond to a phenotypically and
biochemically FAPs-like population of adherent MPCs. These adherent cells respond in
the same fashion to TGF-b signaling and the tyrosine kinase inhibitor Nilotinib as FAPs.
3. The role and/or cross-talk of TGF-b signaling in the regulation of PDGFRa expression
and signaling in mesenchymal progenitors is described: i) PDGFRa expression is strongly
reduced by TGF-b signaling in FAPs, Hic1+ MPs, skin fibroblasts, and two different MPs
cell lines. ii) PDGFRa-mediated gene expression is altered during muscle regeneration in
FAPs and after TGF-b1 treatment. iii) Pharmacological inhibition of PDGFRa impaired the
TGF-b-mediated ECM remodeling and blocked the TGF-b1-induced migration of MPs. 4.
the ubiquitin-proteasome system (UPS). Via Tcf7l2 pharmacological inhibition we suggest
that Tcf7l2 plays a role in regulating FAPs survival and fate.
Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and
signaling governing pathways might be suitable for a novel therapeutic target for the
treatment of MD, neurodegenerative diseases, non-malignant fibroproliferative disorders,
and aging.Fibrosis, the dysregulated accumulation of connective tissue (CT), is a hallmark of
multiple pathologies where inflammation is not fully resolved. The main components of
the CT are the extracellular matrix (ECM) and its tissue-resident mesenchymal stromal
cells (MSCs), which actively produce and remodel ECM during development,
homeostasis, and disease. Fibrosis and/or fibro-fatty replacement of the functional tissue
is a common feature of Duchenne Muscular Dystrophy (DMD), but it is also observed in
neuromuscular diseases. It is generally accepted that these mesenchymal progenitor cells
(MPCs) [hereafter referred to as fibro/adipogenic progenitors (FAPs)] are the progenitors
of pathological myofibroblasts and adipocytes during muscular dystrophy and chronic
muscle damage, but also important players for proper tissue regeneration. Their
dysregulated activity during pathology impairs proper tissue repair. Our overall hypothesis
is that efficient regeneration depends on a complex network of signaling interactions
between multiple cell types leading to the proper coordination of their function.
The best-known marker for FAPs is the receptor tyrosine kinase (RTK) plateletderived growth factor receptor alpha (PDGFRa). Several attempts to block the
dysregulated RTK activity of PDGFRa in pathology have been successfully done,
therefore, PDGFRa signaling emerges as a potential target against fibrosis. TGF-bmediated signaling pathways are commonly accepted to be fibrotic, to induce the
proliferation of FAPs and myofibroblast differentiation from these precursors. TGF-b
signaling and its ligands are augmented during DMD, and fibrosis in several tissues.
Hence, TGF-b is a known driver of the fibrotic process. Here, we investigated the role of
TGF-b signaling on PDGFRa expression and signaling, along with studying a functional
cross-talk between PDGFRa and TGF-b in FAPs and MPCs.
Canonical Wnt Tcf/Lef transcription factors are important players during
development and controlling stem cell fate. Recently, the canonical Wnt signaling cascade
emerged as a new system to study fibrosis in several tissues. Importantly, the role of
Tcf/lef proteins in MPCs has not been studied yet. Additionally, whether TGF-b has an
impact on Wnt signaling and/or may crosstalk through the regulation of these Wnt
transcription factors has not been explored yet.
In the present Ph.D. thesis, we focused on the TGF-b signaling pathway and its
role in FAPs and MPCs. The main findings are; 1. MPCs are present in skeletal muscle
under normal conditions and are increased in several models where muscle fibrosis and
TGF-b are a hallmark. These Tcf7l2+ progenitors lie near macrophages mainly
concentrated in dystrophic necrotic-regenerating foci. 2. We suggest that the historically
named muscle CT fibroblasts isolated via pre-plating correspond to a phenotypically and
biochemically FAPs-like population of adherent MPCs. These adherent cells respond in
the same fashion to TGF-b signaling and the tyrosine kinase inhibitor Nilotinib as FAPs.
3. The role and/or cross-talk of TGF-b signaling in the regulation of PDGFRa expression
and signaling in mesenchymal progenitors is described: i) PDGFRa expression is strongly
reduced by TGF-b signaling in FAPs, Hic1+ MPs, skin fibroblasts, and two different MPs
cell lines. ii) PDGFRa-mediated gene expression is altered during muscle regeneration in
FAPs and after TGF-b1 treatment. iii) Pharmacological inhibition of PDGFRa impaired the
TGF-b-mediated ECM remodeling and blocked the TGF-b1-induced migration of MPs. 4.
the ubiquitin-proteasome system (UPS). Via Tcf7l2 pharmacological inhibition we suggest
that Tcf7l2 plays a role in regulating FAPs survival and fate.
Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and
signaling governing pathways might be suitable for a novel therapeutic target for the
treatment of MD, neurodegenerative diseases, non-malignant fibroproliferative disorders,
and aging.Fibrosis, the dysregulated accumulation of connective tissue (CT), is a hallmark of
multiple pathologies where inflammation is not fully resolved. The main components of
the CT are the extracellular matrix (ECM) and its tissue-resident mesenchymal stromal
cells (MSCs), which actively produce and remodel ECM during development,
homeostasis, and disease. Fibrosis and/or fibro-fatty replacement of the functional tissue
is a common feature of Duchenne Muscular Dystrophy (DMD), but it is also observed in
neuromuscular diseases. It is generally accepted that these mesenchymal progenitor cells
(MPCs) [hereafter referred to as fibro/adipogenic progenitors (FAPs)] are the progenitors
of pathological myofibroblasts and adipocytes during muscular dystrophy and chronic
muscle damage, but also important players for proper tissue regeneration. Their
dysregulated activity during pathology impairs proper tissue repair. Our overall hypothesis
is that efficient regeneration depends on a complex network of signaling interactions
between multiple cell types leading to the proper coordination of their function.
The best-known marker for FAPs is the receptor tyrosine kinase (RTK) plateletderived growth factor receptor alpha (PDGFRa). Several attempts to block the
dysregulated RTK activity of PDGFRa in pathology have been successfully done,
therefore, PDGFRa signaling emerges as a potential target against fibrosis. TGF-bmediated signaling pathways are commonly accepted to be fibrotic, to induce the
proliferation of FAPs and myofibroblast differentiation from these precursors. TGF-b
signaling and its ligands are augmented during DMD, and fibrosis in several tissues.
Hence, TGF-b is a known driver of the fibrotic process. Here, we investigated the role of
TGF-b signaling on PDGFRa expression and signaling, along with studying a functional
cross-talk between PDGFRa and TGF-b in FAPs and MPCs.
Canonical Wnt Tcf/Lef transcription factors are important players during
development and controlling stem cell fate. Recently, the canonical Wnt signaling cascade
emerged as a new system to study fibrosis in several tissues. Importantly, the role of
Tcf/lef proteins in MPCs has not been studied yet. Additionally, whether TGF-b has an
impact on Wnt signaling and/or may crosstalk through the regulation of these Wnt
transcription factors has not been explored yet.
In the present Ph.D. thesis, we focused on the TGF-b signaling pathway and its
role in FAPs and MPCs. The main findings are; 1. MPCs are present in skeletal muscle
under normal conditions and are increased in several models where muscle fibrosis and
TGF-b are a hallmark. These Tcf7l2+ progenitors lie near macrophages mainly
concentrated in dystrophic necrotic-regenerating foci. 2. We suggest that the historically
named muscle CT fibroblasts isolated via pre-plating correspond to a phenotypically and
biochemically FAPs-like population of adherent MPCs. These adherent cells respond in
the same fashion to TGF-b signaling and the tyrosine kinase inhibitor Nilotinib as FAPs.
3. The role and/or cross-talk of TGF-b signaling in the regulation of PDGFRa expression
and signaling in mesenchymal progenitors is described: i) PDGFRa expression is strongly
reduced by TGF-b signaling in FAPs, Hic1+ MPs, skin fibroblasts, and two different MPs
cell lines. ii) PDGFRa-mediated gene expression is altered during muscle regeneration in
FAPs and after TGF-b1 treatment. iii) Pharmacological inhibition of PDGFRa impaired the
TGF-b-mediated ECM remodeling and blocked the TGF-b1-induced migration of MPs. 4.
the ubiquitin-proteasome system (UPS). Via Tcf7l2 pharmacological inhibition we suggest
that Tcf7l2 plays a role in regulating FAPs survival and fate.
Therefore, in this Ph.D. Thesis we studied and proposed that FAPs modulators and
signaling governing pathways might be suitable for a novel therapeutic target for the
treatment of MD, neurodegenerative diseases, non-malignant fibroproliferative disorders,
and aging.
Description
Tesis (Doctor of Philosophy in Biological Sciences with mention in Cell and Molecular Biology)--Pontificia Universidad CatĆ³lica de Chile, 2019