If you have an accident, calling 911, or your local equivalent, will get you the paramedics. In case of neural injury, dialing up SDF-1 might get you a dose of much-needed stem cells, while class 1 MHC molecules might be just what you need to help repair damaged neurons. So conclude two very different, though equally intriguing reports in last week’s early online edition of PNAS. The findings could have a significant impact on the development of potential treatments to repair or prevent neuronal damage.
What impels stem cells to migrate relatively vast distances? The answers have not come readily, but the fact that stem cells always end up at sites of repair put Samia Khuory and colleagues at Brigham and Women’s Hospital, Boston, on to SDF-1Aα (stromal-derived factor 1Aα), a chemoattractant.
First author Jaime Imitola and colleagues, including Brigham’s Evan Snyder and Christopher Walsh at Beth Israel Deaconess Medical Center, also in Boston, reasoned that stem cells home in on damaged tissue of various types because they all have something in common—inflammation. To test this theory, the authors examined how human neural stem cells (hNSCs) respond to SDF-1Aα, a protein that is released by glia and immune cells and has been shown to induce migration of leukocytes and hematopoietic precursors. When the authors added SDF-1Aα to cultures of stem cells, it induced their proliferation. In addition, Imitola found the factor boosted “slide and glide,” a documented behavior whereby stem cells use each other as a supporting chain-like framework for migration. SDF-1Aα, in fact, almost doubled the distance the cells migrated, and tripled it in the presence of basic fibroblast growth factor (bFGF).
It is known that SDF-1Aα is the only ligand for the cell surface receptor CXC chemokine receptor 4 (CXCR4). If SDF-1Aα were the true beacon for stem cell migration, then CXCR4 might be required for the homing process. To test this, Imitola and colleagues first looked for CXCR4 in hNSCs, finding that the protein was indeed expressed in several undifferentiated stem cell lines and in sites of neurogenesis, including fetal mouse ventricular zone and the adult subventricular zone. Also, when the authors exposed hNSCs to SDF-1Aα, it triggered a CXCR4-mediated signaling response, leading to activation of proteins known to be involved in migration, including phosphorylation of p38MAPK, c-jun, and paxilin.
But is this SDF-1Aα/ CXCR4 relationship physiologically relevant? To test this, the authors examined how stem cells migrate in mice suffering from an ischemic injury. When Imitola and colleagues planted hNSCs in the brain, on both the contra- and ipsilateral side to the injury, the cells migrated to the ischemic site. In fact, cortical sections showed that the number of migrating cells was directly proportional to levels of SDF-1Aα.
Examining this in a slightly different way, Imitola measured what impact explants from the injured brain sites would have on NSCs cultured from mouse subventricular zone. When incubated together, the NSCs were found to migrate aggressively toward, and onto, the explants. Tissue from non-ischemic animals had no such effect. Adding CXCR4 antibodies to the mix dramatically reduced (by about 90 percent) the numbers of NSCs attracted to the explants. This later observation would seem to confirm that the chemokine receptor is involved in the process.
All told, the experiments make a strong case for SDF-1Aα/CXCR4 as a major signaling mechanism that guides neuronal stem cells to sites of injury, a finding that could have clinical implications for treating not only stroke treatment, but also neurodegenerative disease. In addition, as the authors point out, the results suggest that “inflammation may be viewed as playing more than its commonly recognized adverse role in the CNS and other organs, but as also providing stimuli that call in ‘homeostasis-promoting’ cells.”
Class I MHC Molecules and Axon Repair
MHC I (major histocompatibility complex, class I) molecules have, of course, been associated with immune and inflammatory responses for years. Recently, however, Carla Shatz and colleagues at Harvard Medical School reported an altogether different role for MHC I molecules, one in neuronal development and plasticity (see Huh et al., 2000). Now, Staffan Cullheim and colleagues at the Karolinska Institute in Stockholm, Sweden, report that MCH I molecules may also play a crucial role in neuronal repair.
First author Alexandre Oliveira and colleagues studied regeneration of sciatic motor neurons in TAP-1 (transporter associated with antigen processing 1)-null mice. In these animals, expression of MHC I molecules at the cell surface is severely impaired.
After a traumatic neuronal injury, such as severing of an axon, a typical neuronal response is the detachment of synapses from the dendrites and neuronal cell body. While the synaptic density, as judged by immunoreactivity, was normal in the TAP-1 animals, Oliveira found that this detachment was exacerbated in these animals, as compared to controls, after the sciatic motor neuron was severed. The findings indicate that MHC expression is necessary to slow, or maybe even prevent loss of synapses.
To investigate this more fully, the authors examined what types of synapses are most affected. Several types of synaptic terminals can be distinguished by microscopy. Of these, the S-type, which harbors glutamate, is generally considered excitatory, and the F-type, which harbors glycine, is thought to be inhibitory. Oliveira found that in the TAP-1-null animals, the F-type synapses were preferentially lost. F synaptic boutons fell by about 60 percent when neurons in TAP-1-null mice were severed, but only by about 40 percent in wild-type animals (a statistically significant difference), while there was no statistical difference between the numbers of S synaptic boutons lost.
What does this mean for the ability of neurons to regenerate after injury? To answer this, the authors tested regeneration after a 1-mm-long resection of the sciatic nerve. Though equal numbers of neurons in wild-type and TAP-1-negative animals survived three weeks after the insult, fewer neuronal cell bodies regained connections with their distal ends in the mutant animals.
The authors conclude that “MHC class I molecules, traditionally viewed as solely involved in immunorecognition, play an important role for stabilizing specific synaptic contacts in the adult nervous system after lesion, which may in turn be important for the ability of lesioned neurons to generate new axons after axotomy.”—Tom Fagan
- Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science. 2000 Dec 15;290(5499):2155-9. PubMed.
No Available Further Reading
- Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, Lindå H, Cullheim S. A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17843-8. PubMed.
- Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18117-22. PubMed.