Neural Progenitors Talk Back to Microglia

When it comes to the molecular conversation between the cells that could become neurons and the brain’s microglia, scientists have mostly eavesdropped on the signals sent out by the microglia. But it turns out the other side—the neural progenitor cells (NPCs)—has plenty to say, too, and microglia respond by activating and reproducing. “NPCs orchestrate the local immune environment in the brain by talking to microglia,” concluded senior author Tony Wyss-Coray, who led the team at Stanford University in Palo Alto, California, that published the data today in Nature Neuroscience online.

The finding may explain how transplanted stem cells can support the brain, even if they create few new neurons. Neural stem cell transplants benefit mice modeling multiple sclerosis (see ARF related news story on Pluchino et al., 2003) or spinal cord injury (Ziv et al., 2006). However, few of the transplanted cells themselves survive, Wyss-Coray said, so the way the treatment works has been a mystery.

Microglia do affect NPCs in their niche. For example, inflammation can repress the production of new neurons (see ARF related news story on Monje et al., 2003, and Ekdahl et al., 2003). Aging can produce such inflammation, and neurodegeneration affects neurogenesis as well (Winner et al., 2011). But few researchers have switched the question around to ask not how the niche affects NPCs, but how NPCs affect their cellular environment. Wyss-Coray and co-senior author Raphael Guzman, who has moved from Stanford to the University of Basel in Switzerland, noticed that the NPC niche contains a hefty population of microglia, even in healthy mouse brains. The close association between the two cell types suggested to them that microglia might not always be repressors of neurogenesis.

To find out what the NPCs tell the microglia, joint first authors Kira Mosher, Robert Andres, and Takeshi Fukuhara first profiled the secretome of mouse NPC primary cultures. They identified dozens of output molecules. Several were known regulators of microglia and immunity. Vascular endothelial growth factor was one secreted factor they noticed. “[NPCs] are engines of VEGF production,” Wyss-Coray said. “It was just stunning how much they made.” VEGF is known to promote the growth of blood vessels and protect neurons.

Next, Andres—since moved to the University of Berne in Switzerland—and colleagues collected the media from cultured NPCs and applied it to cultured microglia. When exposed to the NPCs' signals, the microglia turned up proliferation. They were also more likely to crawl through the filter in a divided chamber, mimicking their ability in situ to home in on sites of injury in the brain. These activated microglia also gobbled up latex beads in a manner akin to the phagocytosis they perform in the body.

NPC signals produced similar effects in vivo. Takeshi—now at the Tokyo University of Pharmacy and Life Sciences in Japan—and coauthors discovered this when they injected NPCs or NPC-conditioned media into the striata of mice. The injected areas contained more active, proliferating microglia than striata that received control injections of saline or unconditioned media.

The team further investigated the role of VEGF in the cocktail of factors secreted by NPCs. By itself, recombinant VEGF promoted microglial proliferation in culture and in vivo. Removing VEGF by immunoprecipitation or silencing RNA treatment rendered the conditioned media less effective on microglia both in vitro and in vivo. VEGF is not the only important component of the NPC secretome, but is a major one, Wyss-Coray said.

The results suggest that NPCs are not merely a reservoir for new neurons, but may actively influence immune activity. Perhaps they activate microglia to act as phagocytes and clean up the niche, Wyss-Coray hypothesized.

In essence, this crosstalk between progenitors and microglia may act as a “bonus” feature in stem cell transplant therapy, suggested Henriette van Praag of the National Institute on Aging in Bethesda, Maryland. By regulating microglial activity, stem cells might be able to promote recovery from injury or illness even if the transplants themselves do not divide much. NPCs might also use VEGF and other factors to support their own survival, van Praag suggested.—Amber Dance

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References

News Citations

  1. Adult Stem Cells Target Inflammation, Replace Cells in MS Model
  2. Antiinflammatory Drugs Protect Hippocampal Neurogenesis

Paper Citations

  1. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003 Apr 17;422(6933):688-94. PubMed.
  2. Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13174-9. PubMed.
  3. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003 Dec 5;302(5651):1760-5. PubMed.
  4. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13632-7. PubMed.
  5. Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci. 2011 Mar;33(6):1139-51. PubMed.

Further Reading

Papers

  1. Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011 May 26;70(4):687-702. PubMed.
  2. Ekdahl CT. Microglial activation - tuning and pruning adult neurogenesis. Front Pharmacol. 2012;3:41. PubMed.
  3. Lee SW, Clemenson GD, Gage FH. New neurons in an aged brain. Behav Brain Res. 2012 Feb 14;227(2):497-507. PubMed.
  4. Klassen HJ, Imfeld KL, Kirov II, Tai L, Gage FH, Young MJ, Berman MA. Expression of cytokines by multipotent neural progenitor cells. Cytokine. 2003 May;22(3-4):101-6. PubMed.
  5. Voloboueva LA, Giffard RG. Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res. 2011 Dec;89(12):1989-96. PubMed.

Primary Papers

  1. Mosher KI, Andres RH, Fukuhara T, Bieri G, Hasegawa-Moriyama M, He Y, Guzman R, Wyss-Coray T. Neural progenitor cells regulate microglia functions and activity. Nat Neurosci. 2012 Oct 21; PubMed.

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