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Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma

Hawthorne, Ian J. ; Dunbar, Hazel ; Tunstead, Courteney ; Schorpp, Tamara ; Weiss, Daniel J. ; Enes, Sara Rolandsson LU orcid ; dos Santos, Claudia C. ; Armstrong, Michelle E. ; Donnelly, Seamas C. and English, Karen (2023) In Molecular Therapy 31(11). p.3243-3258
Abstract

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs... (More)

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
allergic asthma, cyclooxygenase, house dust mite, macrophage migration inhibitory factor, mesenchymal stromal cells
in
Molecular Therapy
volume
31
issue
11
pages
16 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:37735872
  • scopus:85173044469
ISSN
1525-0016
DOI
10.1016/j.ymthe.2023.09.013
language
English
LU publication?
yes
id
fb51953b-2a68-431e-849c-16441c0e55ac
date added to LUP
2023-12-19 14:33:34
date last changed
2024-04-18 01:38:02
@article{fb51953b-2a68-431e-849c-16441c0e55ac,
  abstract     = {{<p>Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT<sub>7</sub> mice but not in CATT<sub>5</sub> or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT<sub>7</sub> mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT<sub>6/7/8</sub>).</p>}},
  author       = {{Hawthorne, Ian J. and Dunbar, Hazel and Tunstead, Courteney and Schorpp, Tamara and Weiss, Daniel J. and Enes, Sara Rolandsson and dos Santos, Claudia C. and Armstrong, Michelle E. and Donnelly, Seamas C. and English, Karen}},
  issn         = {{1525-0016}},
  keywords     = {{allergic asthma; cyclooxygenase; house dust mite; macrophage migration inhibitory factor; mesenchymal stromal cells}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{3243--3258}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Therapy}},
  title        = {{Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma}},
  url          = {{http://dx.doi.org/10.1016/j.ymthe.2023.09.013}},
  doi          = {{10.1016/j.ymthe.2023.09.013}},
  volume       = {{31}},
  year         = {{2023}},
}