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Journal Club
Experimental Paper of the Month - Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion
Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion

Publishing date: May 2022

Author(s): Lili Xie (1,2), Ling-Ping Cen (1,2 3), Yiqing Li (1,2,4), Hui-Ya Gilbert (1,2), Oleksandr Strelko (1,2), Cynthia Berlinicke (5,6,7,8), Mihaela A Stavarache (9), Madeline Ma (1,2), Yongting Wang (10), Qi Cui (1,2,3), Michael G Kaplitt (9), Donald J Zack (5,6,7,8), Larry I Benowitz (1,2,11,12), Yuqin Yin (1,2)

1 Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
2 F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
3 Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou 515000, China.
4 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510085, China.
5 Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
6 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
7 Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
8 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
9 Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065.
10 School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
11 Department of Ophthalmology, Harvard Medical School, Boston, MA 02115.
12 Program in Neuroscience, Harvard Medical School, Boston, MA 02115.

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell–derived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels.

Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.

Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2113751119. doi: 10.1073/pnas.2113751119. Epub 2022 Apr 8.

PMID: 35394873 DOI: 10.1073/pnas.2113751119


Keywords: RGC subtypes; SDF1; inflammation; macrophages; optic nerve regeneration



Experimental Paper of the Month manager: Anthony Khawaja
Editorial Board: Humma Shahid, Karl Mercieca, Francisco Goni
Editors in Chief: Francesco Oddone, Manuele Michelessi




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