title: Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization.
abstract: OBJECTIVE
  Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow-derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV.
  
  
  METHODS
  Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+).
  
  
  RESULTS
  Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells.
  
  
  CONCLUSIONS
  Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization.
authors.affiliation: The Duke Center for Macular Diseases, Duke Eye Center, Durham, North Carolina.
authors.forename: Diego G
authors.initials: DG
authors.lastname: Espinosa-Heidmann
authors.forename: Goldis
authors.initials: G
authors.lastname: Malek
authors.forename: Priyatham S
authors.initials: PS
authors.lastname: Mettu
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caicedo
authors.forename: Peter
authors.initials: P
authors.lastname: Saloupis
authors.forename: Sarah
authors.initials: S
authors.lastname: Gach
authors.forename: Askia K
authors.initials: AK
authors.lastname: Dunnon
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Spiga
authors.forename: Scott W
authors.initials: SW
authors.lastname: Cousins
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation / Q000379:methods*; D002454:Cell Differentiation; D020256:Choroidal Neovascularization / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000209:etiology / Q000473:pathology / Q000601:surgery*; D051379:Mice; D008810:Mice, Inbred C57BL
keywords: age-related macular degeneration; bone marrow transplantation; bone marrow–derived perivascular precursor cells; experimental choroidal neovascularization; neovascular remodeling