Molecular determinants of airway smooth muscle cells in health and disease
The review article entitled “A narrative review of research advances in the study of molecular markers of airway smooth muscle cells” by Yu et al. (1) aims to summarize the molecular markers for airway smooth muscle cells (ASMCs) in the pathophysiological condition of airway remodeling in asthma. Identification and characterization of the molecular markers, especially related to ASMCs hold a novel gateway for early prognosis of airway remodeling during asthma progression. The current review provides a thorough compilation of smooth muscle specific markers during the different phases of ASMCs growth. Further, identification of these markers holds the key to the ASMCs phenotypic changes like contractile to non-contractile, non-proliferative to proliferative, and smooth-muscle to fibroblast (2), which altogether provides a cellular environment for the management of asthma pathophysiology.
It is a well-recognized fact that ASMCs present as a circular shape to the bronchial tree, plays a very crucial role in regulating airway structure and function, by controlling bronchomotor tone and airway caliber (3-5). Further, as mentioned in this review during airway remodeling it is very hard to identify the origin of the thickened airway and its properties. However, the recent research development in the field of airway remodeling shows that ASMCs from asthmatics proliferate faster compared to non-asthmatics (6-10). This is further supported by in vivo studies using a mouse model of asthma showed an increased airway smooth muscle (ASM) layer thickness (11-13). Further, increased ASM mass due to increased ASMC proliferation, hypertrophy, and migration observed in asthmatics (6,14,15). All these evidences conflicts with the sentence mentioned in this review, “bronchial biopsies from asthmatic and non-asthmatic patients have no significant difference in ASMCs proliferation”.
α-smooth muscle actin (α-SMA), appears to be a very important molecular marker for the identification of the ASMCs (16). The notable caveat with considering α-SMA as a specific smooth muscle marker is that during the phenotype changes of ASMCs to fibroblast the expression levels of α-SMA are shown to be significantly higher (17). Accordingly, the α-SMA as ASMCs marker may lead to misdiagnosis during airway remodeling with pulmonary fibrosis and carefully investigated.
This review elaborates on numerous molecular markers which are favorable for the comprehensive study of the increased ASMCs in asthmatic airway remodeling. This information is supported by the bench studies establishing the markers of ASMCs through semi-quantitative studies like western blotting, immunofluorescence staining, and northern blot analysis with conjunction by using primary cultures of myocytes (18). Amongst the multiple ASMCs markers, MYH11 is considered a molecular marker for mature SMCs, and TAGLN is an early marker for differentiation. A rare variant of MYH11, R247C, has been shown to alter the myosin contractile function and smooth muscle cells (SMCs) phenotype, leading to increased proliferation in vitro. Similarly, the mutation in the corresponding amino residue in MYH7, R249Q, causes familial hypertrophic cardiomyopathy (19). Myh11, which is a very important contractile protein expressed only in SMCs gained importance in generating smooth muscle-specific knockout animals using the Cre-loxP recombinant technique (20). This review comprehensively provided information on all the primary molecular markers (Myosin heavy chain 11, Transgelin, Calponin 1, α-SMA, h-caldesmon, Smooth muscle cell differentiation-specific protein, Desmin and Cysteine- and glycine-rich protein 1) of ASMCs. Further, we wish to point out that Tropomyosin (Tm), which is also one of the major components of smooth muscle phenotype (21) and can be used as a marker of mature differentiated ASMCs. Further, we would like to add a note that, Ki67 is reported as an important proliferative marker in ASMCs in asthmatic conditions (22,23). Additionally, Ki67 is also identified as a crucial marker for mitosis because of its involvement in various phases of the cell cycle (15,24).
Overall, this article provides valuable information regarding the different molecular markers for the identification of stages of ASMCs differentiation. Further, this review will significantly increase the knowledge about molecular markers of ASMCs, which can enhance our knowledge of the phenotypic behavior of ASM and assist in easy diagnosis and management of asthma.
Acknowledgments
Funding: This study was supported by NIH grant R01-HL146705 (to VS) and AHA postdoctoral grant FAR0035454 (to NSA).
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4478/coif). VS reports NIH grant R01-HL146705. NSA reports AHA postdoctoral grant FAR0035454. The other author has no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Yu L, Qiu C, Chen R. A narrative review of research advances in the study of molecular markers of airway smooth muscle cells. Ann Transl Med 2022;10:375. [Crossref] [PubMed]
- Wright DB, Trian T, Siddiqui S, et al. Phenotype modulation of airway smooth muscle in asthma. Pulm Pharmacol Ther 2013;26:42-9. [Crossref] [PubMed]
- Yan F, Gao H, Zhao H, et al. Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease. J Transl Med 2018;16:262. [Crossref] [PubMed]
- Bhallamudi S, Connell J, Pabelick CM, et al. Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2020;318:L112-24. [Crossref] [PubMed]
- Ambhore NS, Kalidhindi RSR, Sathish V. Sex-Steroid Signaling in Lung Diseases and Inflammation. Adv Exp Med Biol 2021;1303:243-73. [Crossref] [PubMed]
- Ambhore NS, Katragadda R, Raju Kalidhindi RS, et al. Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation. Mol Cell Endocrinol 2018;476:37-47. [Crossref] [PubMed]
- Wei L, Gou X, Su B, et al. Mahuang Decoction Attenuates Airway Inflammation and Remodeling in Asthma via Suppression of the SP1/FGFR3/PI3K/AKT Axis. Drug Des Devel Ther 2022;16:2833-50. [Crossref] [PubMed]
- Defnet AE, Huang W, Polischak S, et al. Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation. FASEB J 2019;33:10833-43. [Crossref] [PubMed]
- Black JL, Johnson PR, Armour CL. Factors controlling transduction signaling and proliferation of airway smooth muscle. Curr Allergy Asthma Rep 2001;1:116-21. [Crossref] [PubMed]
- Johnson PR, Roth M, Tamm M, et al. Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001;164:474-7. [Crossref] [PubMed]
- Defnet AE, Shah SD, Huang W, et al. Dysregulated retinoic acid signaling in airway smooth muscle cells in asthma. FASEB J 2021;35:e22016. [Crossref] [PubMed]
- Ambhore NS, Kalidhindi RSR, Loganathan J, et al. Role of Differential Estrogen Receptor Activation in Airway Hyperreactivity and Remodeling in a Murine Model of Asthma. Am J Respir Cell Mol Biol 2019;61:469-80. [Crossref] [PubMed]
- Kalidhindi RSR, Ambhore NS, Balraj P, et al. Androgen receptor activation alleviates airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma. Am J Physiol Lung Cell Mol Physiol 2021;320:L803-18. [Crossref] [PubMed]
- Ambhore NS, Kalidhindi RSR, Pabelick CM, et al. Estrogen regulates lamellipodial and focal adhesion dynamics in airway smooth muscle cell migration. Am J Respir Crit Care Med 2021;203:A4482.
- Borkar NA, Ambhore NS, Kalidhindi RSR, et al. Kisspeptins inhibit human airway smooth muscle proliferation. JCI Insight 2022;7:152762. [Crossref] [PubMed]
- Rosethorne EM, Charlton SJ. Airway remodeling disease: primary human structural cells and phenotypic and pathway assays to identify targets with potential to prevent or reverse remodeling. J Exp Pharmacol 2018;10:75-85. [Crossref] [PubMed]
- Hinz B, Celetta G, Tomasek JJ, et al. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell 2001;12:2730-41. [Crossref] [PubMed]
- Halayko AJ, Salari H. Markers of airway smooth muscle cell phenotype. Am J Physiol 1996;270:L1040-51. [PubMed]
- Kuang SQ, Kwartler CS, Byanova KL, et al. Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells. Circ Res 2012;110:1411-22. [Crossref] [PubMed]
- Chen SR, Liu YX. Myh11-Cre is not limited to peritubular myoid cells and interaction between Sertoli and peritubular myoid cells needs investigation. Proc Natl Acad Sci U S A 2016;113:E2352. [Crossref] [PubMed]
- Vrhovski B, McKay K, Schevzov G, et al. Smooth muscle-specific alpha tropomyosin is a marker of fully differentiated smooth muscle in lung. J Histochem Cytochem 2005;53:875-83. [Crossref] [PubMed]
- Halwani R, Vazquez-Tello A, Sumi Y, et al. Eosinophils induce airway smooth muscle cell proliferation. J Clin Immunol 2013;33:595-604. [Crossref] [PubMed]
- Ceresa CC, Knox AJ, Johnson SR. Use of a three-dimensional cell culture model to study airway smooth muscle-mast cell interactions in airway remodeling. Am J Physiol Lung Cell Mol Physiol 2009;296:L1059-66. [Crossref] [PubMed]
- Hassan M, Jo T, Risse PA, et al. Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma. J Allergy Clin Immunol 2010;125:1037-45.e3. [Crossref] [PubMed]