VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

Sounds extremely useful to us. Nothing will occur with this because we have NO stroke leadership to contact to get followup studies and translational work done. Incompetency in the stroke world in non-action once again. 
http://www.pnas.org/content/early/2016/11/10/1609592113.short

1. Tamar Licht^a,
2. Gadiel Rothe^a,
3. Tirzah Kreisel^a,
4. Brachi Wolf^a,
5. Ofra Benny^b,
6. Alasdair G. Rooney^c,
7. Charles ffrench-Constant^c,
8. Grigori Enikolopov^d,^e, and
9. Eli Keshet^a,¹

Author Affiliations

1. Edited by Fred H. Gage, The Salk Institute for Biological Studies, San Diego, CA, and approved October 14, 2016 (received for review June 15, 2016)

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Significance

Generation of new neurons is maintained in the adult hippocampus throughout life. The process, which is driven by an exhaustible reservoir of neuronal stem cells (NSCs), greatly declines with age, however. We show that even a short, episodic exposure to the angiogenic factor VEGF and a resultant ramification/rejuvenation of the vasculature within the stem cell microenvironment (“niche”) is sufficient for neurogenesis to proceed at a markedly elevated rate for months later without accelerating the rate of NSC depletion. Importantly, this manipulation culminates in marked attenuation of age-dependent neurogenic decline. Long-term neurogenic enhancement via VEGF preconditioning was found to be associated with extensive NSC morphological remodeling resembling a “juvenile” pattern of NSC and blood vessel engagements.

Abstract

Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal “juvenile” NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an “aged” systemic milieu.

• adult neurogenesis
• VEGF
• neurovascular
• aging
• neural stem cells

Footnotes

• ¹To whom correspondence should be addressed. Email: keshet@cc.huji.ac.il.

• Author contributions: T.L. and E.K. designed research; T.L., G.R., T.K., and B.W. performed research; T.K., O.B., A.G.R., C.f.-C., and G.E. contributed new reagents/analytic tools; T.L. and T.K. analyzed data; and T.L. and E.K. wrote the paper.
• The authors declare no conflict of interest.
• This article is a PNAS Direct Submission.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1609592113/-/DCSupplemental.