Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser- induced choroidal neovascularization

Diego Gabriel Espinosa Heidmann, Goldis Malek, Priyatham S. Mettu, Alejandro Caicedo, Peter Saloupis, Sarah Gach, Askia K. Dunnon, Peng Hu, Maria Grazia Spiga, Scott W. Cousins

Research output: Contribution to journalArticle

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Abstract

Purpose. 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.

Original languageEnglish (US)
Pages (from-to)7439-7449
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number12
DOIs
StatePublished - Oct 17 2013

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Choroidal Neovascularization
Bone Marrow Transplantation
Lasers
Bone Marrow
Fibrosis
Endothelial Cells
Green Fluorescent Proteins
Macrophages
Macular Degeneration
Arterioles
Bone Marrow Cells
Smooth Muscle Myocytes
Blood Vessels
Actins
Theoretical Models
Transplantation
Immunohistochemistry
Transplants

Keywords

  • Age-related macular degeneration
  • Bone marrow transplantation
  • Bone marrow-derived perivascular precursor cells
  • Experimental choroidal neovascularization
  • Neovascular remodeling

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser- induced choroidal neovascularization. / Espinosa Heidmann, Diego Gabriel; Malek, Goldis; Mettu, Priyatham S.; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K.; Hu, Peng; Spiga, Maria Grazia; Cousins, Scott W.

In: Investigative Ophthalmology and Visual Science, Vol. 54, No. 12, 17.10.2013, p. 7439-7449.

Research output: Contribution to journalArticle

Espinosa Heidmann, Diego Gabriel ; Malek, Goldis ; Mettu, Priyatham S. ; Caicedo, Alejandro ; Saloupis, Peter ; Gach, Sarah ; Dunnon, Askia K. ; Hu, Peng ; Spiga, Maria Grazia ; Cousins, Scott W. / Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser- induced choroidal neovascularization. In: Investigative Ophthalmology and Visual Science. 2013 ; Vol. 54, No. 12. pp. 7439-7449.
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abstract = "Purpose. 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.",
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T1 - Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser- induced choroidal neovascularization

AU - Espinosa Heidmann, Diego Gabriel

AU - Malek, Goldis

AU - Mettu, Priyatham S.

AU - Caicedo, Alejandro

AU - Saloupis, Peter

AU - Gach, Sarah

AU - Dunnon, Askia K.

AU - Hu, Peng

AU - Spiga, Maria Grazia

AU - Cousins, Scott W.

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Y1 - 2013/10/17

N2 - Purpose. 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.

AB - Purpose. 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.

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