Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo‐obstruction syndrome

Abstract

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo‐obstruction (CIPO) syndrome, a life‐threatening intestinal motility disorder. We showed that CIPO‐SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet‐Derived Growth Factor Receptor‐alpha (PDGFRA) expression. We showed that this modulation occurs without origin‐related differences in CIPO circular and longitudinal‐derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO‐SMC towards an undifferentiated stage. The development of CIPO‐SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.

Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting

“…Interestingly, LIX1 was abnormally expressed in 80% of the mCIPO bowel muscles examined ( N = 20), suggesting that phenotypic switching from contractile to synthetic smooth muscle cells occurs in vivo in people with mCIPO, causing muscle weakness (Pascal De Santa Barbara unpublished data). Consistent with this hypothesis, many pediatric mCIPO colon biopsies had low levels of alpha smooth muscle actin and a 50% reduction in ACTG2 mRNAs [ 31 ]. Furthermore, PDGFRA was expressed at high levels in smooth muscle cells from people with mCIPO.…”

“…When not bound to MRTF, SRF can induce the expression of extracellular matrix (ECM) and pro-mitogenic genes in concert with ELK1 (ETS transcription factor ELK1). This is a potentially important disease mechanism since smooth muscle cells can undergo phenotypic switching from contractile to “synthetic” or “proliferative” state [ 31 ]. This phenotypic switch might also be triggered by mechanical forces [tissue stiffness via Yes1 associated transcriptional regulator (YAP1)] or inflammatory mediators [via nuclear factor kappa B (NFκB)] since YAP1 and NFκB bind to and sequester myocardin (MYOCD), a key transcription factor needed to evoke contractile gene expression in the smooth muscle.…”

Time is Gut. Approaching Intestinal Leiomyositis: Case Presentation and Literature Review

“…ILL is an inflammatory myopathy that belongs to a heterogeneous group of disorders that clinically present as PIPO, according to the diagnostic criteria set by the expert group of ESPGHAN [ 5 7 10 ]. PIPO has also been associated with gene mutations associated with smooth muscle function and structure [ 18 ]. Although T-lymphocytic intestinal leiomyositis (T-ILL) can be classified as primary or secondary when triggering factors such as infections, toxins, or paraneoplastic syndromes are present, little is known about the pathophysiological mechanisms that affect only the intestinal muscular layer [ 8 10 18 19 ].…”

Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

“…The frontostriatal and/or frontocerebellar circuits are an extensive network of interconnected neurons underlying speech and language production for both lexical and semantic categories [ 47 , 48 , 49 ]. Smooth muscle cells, enteric neurons, interstitial cells of Cajal and telocytes of the gastrointestinal tract control the musculature and transmucosal fluid movement of the tract, thus coordinating digestive and motility activity [ 50 , 51 , 52 ] ( Figure 3 ).…”