Biological scaffolds modulate immune cells

RESEARCH HIGHLIGHTS Nature Reviews Immunology | Published online 28 Apr 2016; doi:10.1038/nri.2016.52 T I S S U E R E PA I R Biological scaffolds modulate immune cells macrophages. Expression of the M2 macrophage marker CD206 was lower in the wounds of Rag1–/– mice compared with controls; this pheno­ type was rescued after transfer of wild-type CD4+ T cells but not when mice received TH2‑deficient T cell populations. Furthermore, the gene expression profile associated with scaffold-associated macro­phages was lost in Rag1–/– mice, and the expression of several genes implicated in muscle regeneration was substantially decreased in these mice. In addition, myeloid cells from scaffold-treated Il4–/– mice expressed decreased levels of CD206 compared with those from control mice. Thus, IL‑4 is required for TH2 cell-dependent macrophage polarization to support tissue regeneration. Finally, the authors investigated the functional effects of scaffoldinduced tissue regeneration. After 6 weeks, injured and scaffold-treated wild-type mice could run similar distances as uninjured control mice. However, this effect was abolished in injured and scaffold-treated Rag1–/– mice but the effect was restored after transfer of wild-type CD4+ T cells. Histological analysis showed that injured muscle treated with a tissue-derived ECM scaffold was similar to uninjured muscle after 6 weeks, whereas the injured muscle from Rag1–/– mice showed a defect in tissue regeneration. So, in response to muscle injury, tissue-derived biological scaffolds support muscle regeneration by developing a supportive immune microenvironment that depends on TH2 cells. Elisabeth Kugelberg ORIGINAL ARTICLE Sadtler, K. et al. Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science 352, 366–370 (2016) NATURE REVIEWS | IMMUNOLOGY IL‑4 is required for TH2 celldependent macrophage polarization to support tissue regeneration Getty Images/Thinkstock\John Foxx The immune system has an important role in wound healing and tissue repair, and the use of biomaterial scaffolds is an emerging way to drive immune-mediated tissue regeneration. Now, Sadtler et al. show that, in response to traumatic tissue injury, biological scaffolds induce an immune microenvironment that depends on T helper 2 (TH2) cells to reduce inflammation and support tissue regeneration. The authors induced muscle injury in mice and treated these mice with biological scaffolds composed of collagen or tissue-derived extracellular matrix (ECM) to investigate their immunomodulatory properties. The presence of biological scaffolds in a muscle wound dramatically increased the number of myeloid cells and lymphocytes at the injured site compared with saline-treated control mice. Furthermore, wounds treated with biological scaffolds were associated with an increased ratio of CD4+ T cells to CD8+ T cells. The expression of Il4 — which encodes the canonical TH2 cell cytokine interleukin‑4 (IL‑4) — increased in the presence of scaffolds, and this effect was lost in mice deficient in recombination-activating gene 1 (RAG1), which lack mature B cells and T cells. Furthermore, the expression of genes encoding proteins that are associated with TH1 cell responses, such as interferon-γ, decreased in response to scaffold implantation. Thus, TH2 cells seem to drive the immune microenvironment induced by the biological scaffolds. Biological scaffolds are known to become associated with M2 macro­ phages during tissue regeneration. Indeed, macrophages isolated from the wounds of scaffold-treated mice showed increased expression of hallmark genes of M2 macrophages and more specifically of IL‑4‑activated www.nature.com/nri . d e v r e s e r s t h g i r l l A . d e t i m i L s r e h s i l b u P n a l l i m c a M 6 1 0 2 ©