Ligand-receptor interactomeを用いた疼痛誘導メカニズムの解明

近年データベースに大量に蓄積されつつあるゲノムデータやsingle cell RNA sequencing (scRNA-seq)から得られた遺伝子発現データなどを駆使して色々と推論を進めていく、というバイオインフォ―マティクスの手法は、conventionalなcell biologyになじんできた私には何やら具体性に欠けるような気がして、どうもとっつきにくい感が拭えないのですが、そもそもが複雑系である生体のダイナミズムを総合的に把握するにはこのようなアプローチがふさわしいのかも、と考えています。この論文は、様々な臓器や細胞と、脊髄後根神経節 (DRG)の遺伝子発現プロファイルを用いたligand-receptor interactomeから、主として疼痛の伝達に関与する分子機構を解析したものです。例えば関節リウマチ (RA)患者の滑膜マクロファージのscRNA-seqデータから、RA滑膜マクロファージに特異的に発現しているligandとDRGに発現しているreceptorの情報から、ErbB familyがRAにおける疼痛に関与しているのではないかと推測しています。同様の手法を用いて膵臓癌においても、癌細胞が発現するErbB familyが疼痛に関与しているのではないかとしています。最終的にはErbB familyであるHBEGFをマウスに投与することで疼痛を惹起したり、ErbB familyのantagonistであるlapatinibが疼痛を改善させることで上記推論の妥当性を検証しています。このような種類の研究はどうしても結論があいまいになるのですが、本研究では具体的な分子にまでたどりついたという点で興味深いものとなっています。 

Andi Wangzhou et al., A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets. Science Signaling  16 Mar 2021:

Vol. 14, Issue 674, eabe1648 DOI: 10.1126/scisignal.abe1648

A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets

Chronic pain impairs quality of life, is challenging to treat, and accompanies various diseases. Wangzhou et al. integrated bulk and single-cell RNA sequencing of ligand and receptor gene expression in the dorsal root ganglion (DRG) and various peripheral cell types from humans and mice. Computational analysis of these data enabled the construction of a connectome of potential and cell type–specific interaction points between sensory nerves and innervated tissues. With validation in a mouse model of mechanical pain, their findings suggest that blocking heparin-binding epidermal growth factor (HBEGF) signaling may be a common and effective way to alleviate chronic pain in arthritis, colitis, and pancreatic cancer. The resource and the approach, in general, may be used to predict mechanisms of cell-cell communication between various tissues and cell types. In the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis–associated synovial macrophages, and pancreatic tumor tissue. These maps revealed a common correlation between the abundance of heparin-binding EGF-like growth factor (HBEGF) in peripheral cells with that of its receptor EGFR (a member of the ErbB family of receptors) in DRG neurons. Subsequently, we confirmed that increased abundance of HBEGF enhanced nociception in mice, likely acting on DRG neurons through ErbB family receptors. Collectively, these interactomes highlight ligand-receptor interactions that may lead to treatments for disease-associated pain and, furthermore, reflect the complexity of cell-to-neuron signaling in chronic pain states.

A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets