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VEGF Induces Neuroglial Differentiation in Bone Marrow-Derived Stem Cells and Promotes Microglia Conversion Following Mobilization with GM-CSF

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Abstract

Purpose

Evaluation of potential tropic effects of vascular endothelial growth factor (VEGF) on the incorporation and differentiation of bone-marrow-derived stem cells (BMSCs) in a murine model of anterior ischemic optic neuropathy (AION).

Methods

In the first approach, small-sized subset of BMCs were isolated from GFP donors mice by counterflow centrifugal elutriation and depleted of hematopoietic lineages (Fr25lin-). These cells were injected into a peripheral vein (1 × 106 in 0.2 ml) or inoculated intravitreally (2 × 105) to syngeneic mice, with or without intravitreal injection of 5 μg/2μL VEGF, simultaneously with AION induction. In a second approach, hematopoietic cells were substituted by myelablative transplant of syngeseic GFP + bone marrow cells. After 3 months, progenitors were mobilized with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by VEGF inoculation into the vitreous body and AION induction . Engraftment and phenotype were examined by immunohistochemistry and FISH at 4 and 24 weeks post-transplantation, and VEGF receptors were determined by real time PCR.

Results

VEGF had no quantitative effect on incorporation of elutriated cells in the injured retina, yet it induced early expression of neuroal markers in cells incorporated in the RGC layer and promoted durable gliosis, most prominent perivascular astrocytes. These effects were mediated by VEGF-R1/Flt-1, which is constitutively expresses in the elutriated fraction of stem cells. Mobilization with GM-CSF limited the differentiation of bone marrow progenitors to microglia, which was also fostered by VEGF.

Conclusions

VEGF signaling mediated by Flt-1 induces early neural and sustained astrocytic differentiation of stem cells elutriated from adult bone-marrow, with significant contribution to stabilization retinal architecture following ischemic injury.

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Acknowledgments

Thanks are due to Dr. Saul Sharkis and Dr. Michael Collector for their outstanding support and conceptual contribution to this study. Funding was provided by generous grants from the Leah and Edward M. Frankel Trust for bone marrow transplantation and the Zanvyl and Isabelle Krieger Fund, Baltimore, MD, USA; the Israel Science Foundation (NGC, 1371/08); the Eldor-Metzner Clinician Scientist Award, Chief Scientist, (NGC, 3-3741); Chief Scientist and the Lirot Foundation (NGC, 3-4538), Israel Ministry of Health; Pilot Grant from the North American Neuro-Ophthalmology Society; The Adams Super Center for Brain Research, Tel Aviv University, Israel (NGC); the Clair and Ameddee Maratier Fund to prevent blindness, Tel Aviv University, Israel (NGC, BRAL); Walter Friendliest and Herman Shudder Fund, Tel Aviv University, Israel (NGC), The Lions (BRAL) and Mazritzky Fund (TS), Tel Aviv University, Israel.

The results of this study were presented in part at the Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, USA (ARVO); the Meeting of the Israel Society for Eye and Vision Research, Neve Ilan, Israel (ISVER); the Meeting of the North American Neuro-Ophthalmology Society (NANOS), Tucson, AZ; the Meeting of the International Society for Stem Cell Research (ISSCR), Philadelphia, PA; the Meeting of the Federation of the Israel Societies for Experimental Biology (ILANIT/FISEB), Eilat, Israel.

This work was submitted as partial fulfillment of the requirements for a PhD degree of B.R. Avraham-Lubin and MSc degree of T. Sadikov, Tel Aviv University.

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The authors have no potential conflicts of interest.

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Authors and Affiliations

  1. The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petach Tikva, Israel

    Bat-Chen R. Avraham-Lubin, Nitza Goldenberg-Cohen & Tamilla Sadikov

  2. Frankel Laboratory, Center for Stem Cell Research, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    Nadir Askenasy

  3. Department of Pediatric Ophthalmology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    Nitza Goldenberg-Cohen

  4. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Bat-Chen R. Avraham-Lubin, Nitza Goldenberg-Cohen & Tamilla Sadikov

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  1. Bat-Chen R. Avraham-Lubin
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  4. Nadir Askenasy
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Correspondence to Nitza Goldenberg-Cohen.

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Bat-Chen R. Avraham-Lubin and Nitza Goldenberg-Cohen contributed equally to this study

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Avraham-Lubin, BC.R., Goldenberg-Cohen, N., Sadikov, T. et al. VEGF Induces Neuroglial Differentiation in Bone Marrow-Derived Stem Cells and Promotes Microglia Conversion Following Mobilization with GM-CSF. Stem Cell Rev and Rep 8, 1199–1210 (2012). https://doi.org/10.1007/s12015-012-9396-1

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