Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma.
Mesenchymal stem cells (MSCs) have been suggested to participate in immune regulation and airway repair/remodeling. TGF-β1 is critical in the recruitment of stem/progenitor cells for tissue repair, remodeling, and cell differentiation. In this study, we sought to investigate the role of TGF-β1 in MSC migration in allergic asthma. We examined nestin expression (a marker for MSCs) and TGF-β1 signaling activation in airways in cockroach allergen extract (CRE)-induced mouse models. Compared with control mice, there were increased nestin(+) cells in airways and higher levels of active TGF-β1 in serum and p-Smad2/3 expression in lungs of CRE-treated mice. Increased activation of TGF-β1 signaling was also found in CRE-treated MSCs. We then assessed MSC migration induced by conditioned medium from CRE-challenged human epithelium in air/liquid interface culture in Transwell assays. MSC migration was stimulated by epithelial-conditioned medium, but was significantly inhibited by either TGF-β1-neutralizing Ab or TβR1 inhibitor. Intriguingly, increased migration of MSCs from blood and bone marrow to the airway was also observed after systemic injection of GFP(+) MSCs and from bone marrow of Nes-GFP mice following CRE challenge. Furthermore, TGF-β1-neutralizing Ab inhibited the CRE-induced MSC recruitment, but promoted airway inflammation. Finally, we investigated the role of MSCs in modulating CRE-induced T cell response and found that MSCs significantly inhibited CRE-induced inflammatory cytokine secretion (IL-4, IL-13, IL-17, and IFN-γ) by CD4(+) T cells. These results suggest that TGF-β1 may be a key promigratory factor in recruiting MSCs to the airways in mouse models of asthma.
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Peisong
P
Gao
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Yufeng
Y
Zhou
Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lingling
L
Xian
Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Changjun
C
Li
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ting
T
Xu
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Beverly
B
Plunkett
Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|National Health Research Institutes, Taiwan.
Shau-Ku
SK
Huang
Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mei
M
Wan
Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Xu
X
Cao
D000485:Allergens / Q000276:immunology* / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D003058:Cockroaches; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051899:Smad2 Protein / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
D000485:Allergens; D016207:Cytokines; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1