Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome
Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O’Connell, Chyi-Chia Richard Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm
Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O’Connell, Chyi-Chia Richard Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm
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Research Article Vascular biology

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome

Abstract

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job’s syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α–stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.

Authors

Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua D. Milner, Diego B. López, Michael P. O’Connell, Chyi-Chia Richard Lee, Ian A. Myles, Amy P. Hsu, Alexandra F. Freeman, Steven M. Holland, Guibin Chen, Manfred Boehm

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Figure 7

HIF-1α stabilizers improve angiogenesis and wound healing in AD-HIES mouse model.

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HIF-1α stabilizers improve angiogenesis and wound healing in AD-HIES mou...
(A–C) Structural abnormalities of AD-HIES mouse CAs resemble AD-HIES patients. (A) Left: representative images of the hearts. Left CAs (LCAs) filled with silicon are seen. Right: representative images of CA 3D reconstruction. (B) Increased LCA tortuosity (n = 4). (C) Examples of abnormalities in secondary branches. (D and E) Angiogenesis abnormalities in AD-HIES mice: mice failed to restore blood perfusion after ligation of the femoral artery (FA). (D) Quantification by Doppler imaging (WT, n = 3; AD-HIES, n = 5). (E) Left: Representative images of CD31 staining. Scale bars: 50 µm. Right: quantification of capillary density (n = 3). (F–M) Stabilization of HIF-1α by PHD inhibitors improves angiogenesis and wound healing. Treatment with DMF by gavage: (F) improved recapillarization after FA ligation (left: representative images of CD31 staining, original magnification, ×100; right: quantification of capillary densities, n = 5) and (G) restored growth of teratomas from AD-HIES–derived iPSCs (n = 6). (H–M) Topical treatment with DMF and daprodustat (DD) improved deficient skin-wound healing. (H) Representative images. (I) Quantification of wound closure rates. (n = 8 for no-treatment groups; n = 4 for DMF and DD groups). Slower wound closure in AD-HIES mice was accelerated by DMF and DD. (J–M) Histological analysis of the wounds demonstrating (J) deficient reepithelialization and fibroblast infiltration, (K) increased STAT3 phosphorylation, and (L and M) increased HIF-1α expression by DMF treatment. Representative images and quantification of HIF-1α stainings are shown (n = 4). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired t test (B, D, I, and M), 1-way ANOVA followed by Holm-Šidák multiple comparisons test (E–G). See also Supplemental Figure 12 and Supplemental Videos 1 and 2.