Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis

Abstract

Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related chronic diseases, such as cancer and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells (MSCs) in the terminal airways-alveoli by bronchoalveolar lavage (BAL) of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis (IPF), defined as <5% and ≥10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-β and SHH signaling. Importantly, fibroblast growth factor-10 (FGF-10) was markedly suppressed in IPF subjects with progressive disease, and both TGF-β1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

“…Consequently, perturbation of barrier morphogenesis in childhood may have a lasting effect on adult epithelium via alteration of developmental programs and epigenetic reprogramming at developmental checkpoints 105–107 . Multiple lines of evidence now implicate active re-engagement of morphogenetic programs in adult disease, typically not seen in adult homeostatic tissue 108–110 . Alterations of the Wnt 66 , Hippo 111 , Notch/Jagged 112, 113 and Hedgehog 114 developmental pathways all exhibit strong association with epithelial remodeling and allergy.…”

Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

“…These findings suggest that FGF10-expressing myofibroblasts in IPF may be potentially derived from lipofibroblasts. Interestingly, a recent report characterizing mesenchymal cells in bronco-alveolar lavage (BAL) from progressive versus stable IPF showed a loss of FGF10 transcript and protein expression in progressive IPF mesenchymal cells compared with stable IPF mesenchymal cells[89], indicating a loss of lipofibroblasts or myofibroblasts derived from lipofibroblasts in these patients. Mining of RNAseq datasets from our cultured rapid IPF, slow IPF, and normal lung fibroblasts indicate that there are no significant changes in ADRP transcript but a marked reduction in PPARG and FGF10 transcript expression in both IPF groups compared with normal lung fibroblasts.…”

Characterization of Mesenchymal Stem Cells Derived from Patients with Cerebellar Ataxia: Downregulation of the Anti-Inflammatory Secretome Profile

“…In accordance with previous studies [37,38], our findings suggest a limitation of autologous MSC therapy for CA. Recently, the bone marrow microenvironment and cellular functions were reported to be affected by disease states [39][40][41]. Thus, MSCs from patients with chronic diseases may have reprogrammed gene expression profiles.…”