Chen Wang, MD, PhD

All Publications

• Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases. Nature genetics Ober-Reynolds, B., Wang, C., Ko, J. M., Rios, E. J., Aasi, S. Z., Davis, M. M., Oro, A. E., Greenleaf, W. J. 2023

  Abstract

  Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50-100% more enhancer-gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema.

  View details for DOI 10.1038/s41588-023-01445-4

  View details for PubMedID 37500727

  View details for PubMedCentralID 4006068

• Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome Walker, S., Wang, C., Walradt, T., Hong, B. S., Tanner, J. R., Levinsohn, J., Goh, G., Subtil, A., Lessin, S. R., Heymann, W., Vonderheid, E. C., King, B. A., Lifton, R., Choi, J. ELSEVIER SCIENCE INC. 2016: S5

  View details for DOI 10.1016/j.jid.2016.02.051

  View details for Web of Science ID 000380028800027

• Complement membrane attack complexes activate noncanonical NF-κB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes. Proceedings of the National Academy of Sciences of the United States of America Jane-wit, D., Surovtseva, Y. V., Qin, L., Li, G., Liu, R., Clark, P., Manes, T. D., Wang, C., Kashgarian, M., Kirkiles-Smith, N. C., Tellides, G., Pober, J. S. 2015; 112 (31): 9686-91

  Abstract

  Complement membrane attack complexes (MACs) promote inflammatory functions in endothelial cells (ECs) by stabilizing NF-κB-inducing kinase (NIK) and activating noncanonical NF-κB signaling. Here we report a novel endosome-based signaling complex induced by MACs to stabilize NIK. We found that, in contrast to cytokine-mediated activation, NIK stabilization by MACs did not involve cIAP2 or TRAF3. Informed by a genome-wide siRNA screen, instead this response required internalization of MACs in a clathrin-, AP2-, and dynamin-dependent manner into Rab5(+)endosomes, which recruited activated Akt, stabilized NIK, and led to phosphorylation of IκB kinase (IKK)-α. Active Rab5 was required for recruitment of activated Akt to MAC(+) endosomes, but not for MAC internalization or for Akt activation. Consistent with these in vitro observations, MAC internalization occurred in human coronary ECs in vivo and was similarly required for NIK stabilization and EC activation. We conclude that MACs activate noncanonical NF-κB by forming a novel Akt(+)NIK(+) signalosome on Rab5(+) endosomes.

  View details for DOI 10.1073/pnas.1503535112

  View details for PubMedID 26195760

  View details for PubMedCentralID PMC4534258

• Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2. The Journal of experimental medicine Wang, C., Qin, L., Manes, T. D., Kirkiles-Smith, N. C., Tellides, G., Pober, J. S. 2014; 211 (3): 395-404

  Abstract

  Recruitment of circulating leukocytes into inflamed tissues depends on adhesion molecules expressed by endothelial cells (ECs). Here we report that rapamycin pretreatment reduced the ability of TNF-treated ECs to capture T cells under conditions of venular flow. This functional change was caused by inhibition of TNF-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and could be mimicked by knockdown of mammalian target of rapamycin (mTOR) or rictor, but not raptor, implicating mTORC2 as the target of rapamycin for this effect. Mechanistically, mTORC2 acts through Akt to repress Raf1-MEK1/2-ERK1/2 signaling, and inhibition of mTORC2 consequently results in hyperactivation of ERK1/2. Increased ERK1/2 activity antagonizes VCAM-1 expression by repressing TNF induction of the transcription factor IRF-1. Preventing activation of ERK1/2 reduced the ability of rapamycin to inhibit TNF-induced VCAM-1 expression. In vivo, rapamycin inhibited mTORC2 activity and potentiated activation of ERK1/2. These changes correlated with reduced endothelial expression of TNF-induced VCAM-1, which was restored via pharmacological inhibition of ERK1/2. Functionally, rapamycin reduced infiltration of leukocytes into renal glomeruli, an effect which was partially reversed by inhibition of ERK1/2. These data demonstrate a novel mechanism by which rapamycin modulates the ability of vascular endothelium to mediate inflammation and identifies endothelial mTORC2 as a potential therapeutic target.

  View details for DOI 10.1084/jem.20131125

  View details for PubMedID 24516119

  View details for PubMedCentralID PMC3949571

• Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. The Journal of clinical investigation Wang, C., Yi, T., Qin, L., Maldonado, R. A., von Andrian, U. H., Kulkarni, S., Tellides, G., Pober, J. S. 2013; 123 (4): 1677-93

  Abstract

  Human graft endothelial cells (ECs) can act as antigen-presenting cells to initiate allograft rejection by host memory T cells. Rapamycin, an mTOR inhibitor used clinically to suppress T cell responses, also acts on DCs, rendering them tolerogenic. Here, we report the effects of rapamycin on EC alloimmunogenicity. Compared with mock-treated cells, rapamycin-pretreated human ECs (rapa-ECs) stimulated less proliferation and cytokine secretion from allogeneic CD4+ memory cells, an effect mimicked by shRNA knockdown of mTOR or raptor in ECs. The effects of rapamycin persisted for several days and were linked to upregulation of the inhibitory molecules PD-L1 and PD-L2 on rapa-ECs. Additionally, rapa-ECs produced lower levels of the inflammatory cytokine IL-6. CD4+ memory cells activated by allogeneic rapa-ECs became hyporesponsive to restimulation in an alloantigen-specific manner and contained higher percentages of suppressive CD4+CD25(hi)CD127(lo)FoxP3+ cells that did not produce effector cytokines. In a human-mouse chimeric model of allograft rejection, rapamycin pretreatment of human arterial allografts increased graft EC expression of PD-L1 and PD-L2 and reduced subsequent infiltration of allogeneic effector T cells into the artery intima and intimal expansion. Preoperative conditioning of allograft ECs with rapamycin could potentially reduce immune-mediated rejection.

  View details for DOI 10.1172/JCI66204

  View details for PubMedID 23478407

  View details for PubMedCentralID PMC3613923

• Regulation of maternal phospholipid composition and IP(3)-dependent embryonic membrane dynamics by a specific fatty acid metabolic event in C. elegans. Genes & development Kniazeva, M., Shen, H., Euler, T., Wang, C., Han, M. 2012; 26 (6): 554-66

  Abstract

  Natural fatty acids (FAs) exhibit vast structural diversity, but the functional importance of FA variations and the mechanism by which they contribute to a healthy lipid composition in animals remain largely unexplored. A large family of acyl-CoA synthetases (ACSs) regulates FA metabolism by esterifying FA to coenyzme A. However, little is known about how particular FA-ACS combinations affect lipid composition and specific cellular functions. We analyzed how the activity of ACS-1 on branched chain FA C17ISO impacts maternal lipid content, signal transduction, and development in Caenorhabditis elegans embryos. We show that expression of ACS-1 in the somatic gonad guides the incorporation of C17ISO into certain phospholipids and thus regulates the phospholipid composition in the zygote. Disrupting this ACS-1 function causes striking defects in complex membrane dynamics, including exocytosis and cytokinesis, leading to early embryonic lethality. These defects are suppressed by hyperactive IP(3) signaling, suggesting that C17ISO and ACS-1 functions are necessary for optimal IP(3) signaling essential for early embryogenesis. This study shows a novel role of branched chain FAs whose functions in humans and animals are unknown and uncovers a novel intercellular regulatory pathway linking a specific FA-ACS interaction to specific developmental events.

  View details for DOI 10.1101/gad.187054.112

  View details for PubMedID 22426533

  View details for PubMedCentralID PMC3315117

• Reperfusion injury intensifies the adaptive human T cell alloresponse in a human-mouse chimeric artery model. Arteriosclerosis, thrombosis, and vascular biology Yi, T., Fogal, B., Hao, Z., Tobiasova, Z., Wang, C., Rao, D. A., Al-Lamki, R. S., Kirkiles-Smith, N. C., Kulkarni, S., Bradley, J. R., Bothwell, A. L., Sessa, W. C., Tellides, G., Pober, J. S. 2012; 32 (2): 353-60

  Abstract

  Perioperative nonimmune injuries to an allograft can decrease graft survival. We have developed a model for studying this process using human materials.Human artery segments were transplanted as infrarenal aortic interposition grafts into an immunodeficient mouse host, allowed to "heal in" for 30 days, and then retransplanted into a second mouse host. To induce a reperfusion injury, the healed-in artery segments were incubated for 3 hours under hypoxic conditions ex vivo before retransplantation. To induce immunologic rejection, the animals receiving the retransplanted artery segment were adoptively transferred with human peripheral blood mononuclear cells or purified T cells from a donor allogeneic to the artery 1 week before surgery. To compare rejection of injured versus healthy tissues, these manipulations were combined. Results were analyzed ex vivo by histology, morphometry, immunohistochemistry, and mRNA quantitation or in vivo by ultrasound. Our results showed that reperfusion injury, which otherwise heals with minimal sequelae, intensifies the degree of allogeneic T cell-mediated injury to human artery segments.We developed a new human-mouse chimeric model demonstrating interactions of reperfusion injury and alloimmunity using human cells and tissues that may be adapted to study other forms of nonimmune injury and other types of adaptive immune responses.

  View details for DOI 10.1161/ATVBAHA.111.239285

  View details for PubMedID 22053072

  View details for PubMedCentralID PMC3262100

• Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells. Journal of immunology (Baltimore, Md. : 1950) Fogal, B., Yi, T., Wang, C., Rao, D. A., Lebastchi, A., Kulkarni, S., Tellides, G., Pober, J. S. 2011; 187 (12): 6268-80

  Abstract

  Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4(+) memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC cocultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161(+) T cells), increases expression of FOXP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells.

  View details for DOI 10.4049/jimmunol.1003774

  View details for PubMedID 22084439

  View details for PubMedCentralID PMC3237826

• Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. Journal of immunology (Baltimore, Md. : 1950) Suárez, Y., Wang, C., Manes, T. D., Pober, J. S. 2010; 184 (1): 21-5

  Abstract

  MicroRNAs (miRNAs) pair with target sequences in the 3' untranslated region of mRNAs to posttranscriptionally repress gene expression. In this study, we report that TNF-mediated induction of endothelial adhesion molecules can be regulated by miRNAs that are induced by TNF. Specifically, E-selectin and ICAM-1 are targets of TNF-induced miRNAs miR-31 and miR-17-3p, respectively. Specific antagonism of these TNF-induced miRNAs increased neutrophil adhesion to cultured endothelial cells. Conversely, transfections with mimics of these miRNAs decreased neutrophil adhesion to endothelial cells. These data suggest that miRNAs provide negative feedback control of inflammation.

  View details for DOI 10.4049/jimmunol.0902369

  View details for PubMedID 19949084

  View details for PubMedCentralID PMC2797568