Hedgehog-responsive PDGFRa(+) fibroblasts maintain a unique pool of alveolar epithelial progenitor cells during alveologenesis

Gao, Feng; Li, Changgong; Danopoulos, Soula; Alam, Denise Al; Peinado, Neil; Webster, Sha; Borok, Zea; Kohbodi, Golenaz; Bellusci, Saverio; Minoo, Parviz

doi:10.1016/j.celrep.2022.110608

Cited by 21 publications

(22 citation statements)

References 75 publications

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“…The largest deviation between the controls and mutants in these measurements occurred at PN14, which marks the midpoint in the alveologenesis phase. Still, the severity of hypoplasia here is eclipsed by that seen in Gcre;Tgfbr-f/f induced BPD phenocopies (Gao et al, 2022).…”

Section: Postnatal Inactivation Of Igf1r In Scmf Profoundly Arrests A...mentioning

confidence: 69%

“…Behind the overall process of alveologenesis is a much larger signaling gene regulatory network where several different cell types are involved. Within the mesenchymal cell type only, it is known that blocking IGF1, WNT5a, PDGFa, and TGFb signaling leads to impairment in development of alveoli, though with varying severities (Gao et al, 2022; He et al, 2021; Li et al, 2020; Li et al, 2019; Zhang et al, 2020). The sum of these leads to the construction of the hierarchical regulatory connections of these pathways within SCMF (Fig.7).…”

Section: Discussionmentioning

confidence: 99%

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Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia

Gao

Smith

et al. 2022

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Lung development is precisely controlled by underlying Gene Regulatory Networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants with morbid and sometimes lethal consequences that is characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's-eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with Wnt5a and Fgf10 signaling as the bridge. Consistently, blocking of Wnt5a signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. The new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

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Section: Postnatal Inactivation Of Igf1r In Scmf Profoundly Arrests A...mentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia

Gao

Smith

et al. 2022

Preprint

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“…PDGFRA + fibroblasts support alveolar type 2 (AT2) and alveolar type 1 (AT1) cell differentiation during alveolarization, homeostasis and injury repair (15,42,43,49,50).…”

Section: Loss Of Matrix Fibroblast Function Results In At2 Hyperplasi...mentioning

confidence: 99%

“…PDGFRA + fibroblasts support alveolar type 2 (AT2) and alveolar type 1 (AT1) cell differentiation during alveolarization, homeostasis and injury repair (15, 42, 43, 49, 50). Immunohistochemistry for the AT2 cell marker proSPC and AT1 cell markers HOPX and AGER were performed on control and GATA6 PDGFRAΔ/Δ lungs at PN7 and PN28 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the present organoid studies WNT signaling restored the ability of GATA6 PDGFRAΔ/Δ fibroblasts to support AT1 differentiation. Recent studies demonstrate that Wnt5 a is important for AT1 differentiation and regulates AT2/AT1 balance (50). However, Wnt5a was upregulated at PN28 while the number of AT2 cells was still significantly higher, suggesting that WNT5a alone is not sufficient for AT2 to AT1 differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Matrix fibroblast function during alveolarization is dependent on GATA6

Ushakumary

Green

Riccetti

et al. 2022

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Alveolarization is dependent on myo-, matrix- and lipo- fibroblast functions by interstitial PDGFRa+ fibroblasts. While these fibroblasts are derived from GLI and PDGFRa expressing fibroblasts, the transcriptional control of their functional specification remains unknown. Perinatally, the transcription factor GATA6 is upregulated in PDGFRa+ fibroblasts. To study the role of GATA6 during fibroblast differentiation, we generated PDGFRaCreER/GATA6flx/flx mice and deleted GATA6 in the perinatal period and in adult mice prior to left lobe pneumonectomy. Loss of GATA6 in the PDGFRa+-fibroblasts impaired alveolarization, and extracellular matrix deposition, in association with increased TCF21 expression and lipofibroblast differentiation. Loss of GATA6 in PDGFRa+ fibroblasts resulted in loss of alveolar type 1 (AT1) cells and gain of transitional alveolar type 2 (AT2) cells. Loss of GATA6 was associated with reduced WNT signaling. Restoration of WNT signaling in GATA6 deficient alveolar lung organoids restored AT2 and AT1 cell differentiation. GATA6 induces matrix fibroblast functions and represses lipofibroblast functions, serving as key regulator of fibroblast differentiation during alveolarization and regeneration. Present findings link matrix fibroblast functions with the ability of transitional AT2 cells to differentiate into AT1 cells.

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