Mend the Gap: Pericytes Form Core of Spinal Cord Scars

When tissue tears, the body fills in the gap with a scar. In the case of the spinal cord, that so-called “glial scar” is made mainly of astrocytes—or so neuroscientists believed. According to a paper in today’s Science, pericyte-enwrapping blood vessels near a spinal lesion will differentiate and move toward the injury, forming the core of an astrocyte-coated scar. Without pericytes, the wound is likely to remain a gaping hole.

“The pericyte response is dramatic,” wrote study author Christian Göritz of the Karolinska Institute in Stockholm, Sweden, in an e-mail to ARF. “Many cell types respond in one or another way to injury, but the pericyte response is by far the strongest I have ever seen.” Göritz led the study with senior author Jonas Frisén.

Scars are good, in that they fill in a wound with connective tissue. But they also put a damper on regeneration; in the spinal cord, scars block axons attempting to grow across the lesion. “It will be interesting to further investigate the role of these pericytes…to see the extent to which they contribute to axon regenerative failure in the central nervous system,” commented Ben Barres of Stanford University in Palo Alto, California, in an e-mail to ARF.

Pericytes surround blood vessels and help stabilize them. They form an integral part of the blood-brain barrier. In the central nervous system (CNS), these cells are multipotent, with the ability to differentiate into neural and glial cell types as well as connective tissue such as fibroblasts (Dore-Duffy et al., 2006; Dore-Duffy, 2008; Dore-Duffy et al., 2011). They are found throughout the body, and participate in kidney and liver fibrosis (Pinzani et al., 1992; Lin et al., 2008; Humphreys et al., 2010), as well as skin scarring (Sundberg et al., 1996). The role of pericytes in the spinal cord, however, has been “mysterious,” Barres wrote.

Göritz and Frisén have been studying injury response in several cell types (Meletis et al., 2008; Barnabé-Heider et al., 2010), and in the current study, turned their fate-mapping attention to pericytes. Göritz used Cre recombinase to selectively label the pericytes of mice—specifically, a subclass called perivascular cells—with yellow fluorescent protein (YFP). These pericytes, as well as any of their progeny, would glow yellow, allowing the researchers to track them and estimate their role in scarring. However, the markers used to identify pericytes were insufficient to convince Paula Dore-Duffy of Wayne State University School of Medicine in Detroit, Michigan; she suggested that other cell types might have been labeled, too. If so, then cell types besides pericytes could be contributing to the scar’s core.

After spinal cord lesion, the pericytes proliferated. YFP-labeled cells expanded to more than 25 times their normal numbers within nine days of injury. The descendants of the YFP-tagged cells migrated to the injury site and built an extracellular matrix there.

The core of the scar is traditionally considered to be connective tissue such as fibroblasts, Göritz noted, but the identity of the pericyte-descendant, scar-forming cells is uncertain. More work must be done to determine if the migrating pericytes stay pericyte-like, morph into fibroblasts, or become another cell type, he wrote.

The pericyte-derived cells were the first cells to reach the injury site. Astrocytes also proliferated, but their doubling pales in comparison to the explosion of the pericyte lineage. While astrocytes outnumber pericytes 10 to one in a healthy spinal cord, there were twice as many YFP-tagged cells as astrocytes in the damaged area. Together, the cell types formed a scar with a pericyte-derived center and astrocyte shell.

To confirm the importance of pericytes in scar formation, the researchers modified their mice further. In the new line, the activation of Cre not only turned on YFP in the pericytes, but it also disabled cell division by removing all ras genes. Göritz performed spinal cord hemisections and examined the injury sites 18 weeks later. Compared to control mice with normal pericyte cell division, the modified mice had fewer connective tissue cells in the core of the scar. In one-third of the ras-free mice, the injury did not even seal.

Pericytes also dissociate from blood vessels after traumatic brain injury and stroke, as well as in cases of hypoxia and in a mouse model of multiple sclerosis, Dore-Duffy said, although the mechanism of the migration is unclear (Dore-Duffy et al., 1999; Takahashi et al., 1997; Dore-Duffy et al., 2000; Dore-Duffy and Lamanna, 2007). The study authors suggest that pericyte scar formation may be a general mechanism of wound repair throughout the central nervous system, and perhaps in other organs as well. The next step, Göritz wrote, will be to find ways to modulate pericyte activity to minimize the downsides of scarring.

Pericytes might also play a role in neurodegeneration, Dore-Duffy suggested in an e-mail to ARF. A slowing of vascular activity comes with age, she noted, and pericytes are compromised in conjunction with vascular damage in Alzheimer’s disease. Pericytes contribute to the structure of the vascular system, and a poorly functioning vasculature in amyotrophic lateral sclerosis or multiple sclerosis might prevent neurons from getting the energy supply they need, she speculated.—Amber Dance

Comments

  1. In this paper in Science, Jonas Frisén and colleagues have identified a novel, major cell population in the scar that forms after spinal cord injury, and that has commonly been referred to as the "glial scar." The authors convincingly show that pericytes, normally associated with the vasculature, constitute a large fraction in the scar. This was demonstrated by an elegant cell lineage-tracing experiment in mice. The discovery is not only important for obtaining better insights into which cells populate the scar, but also opens new perspectives for future therapies, as pericytes are controlled by key signaling pathways that are druggable. In this paper, the authors also show that modulation of pericyte recruitment may have effects on the motor deficits observed after the injury, which suggests that efforts to control pericyte recruitment and function may be worthwhile in the quest for future therapies.

    View all comments by Urban Lendahl

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References

Paper Citations

  1. Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab. 2006 May;26(5):613-24. PubMed.
  2. Dore-Duffy P. Pericytes: pluripotent cells of the blood brain barrier. Curr Pharm Des. 2008;14(16):1581-93. PubMed.
  3. Dore-Duffy P, Mehedi A, Wang X, Bradley M, Trotter R, Gow A. Immortalized CNS pericytes are quiescent smooth muscle actin-negative and pluripotent. Microvasc Res. 2011 Jul;82(1):18-27. PubMed.
  4. Pinzani M, Abboud HE, Gesualdo L, Abboud SL. Regulation of macrophage colony-stimulating factor in liver fat-storing cells by peptide growth factors. Am J Physiol. 1992 Apr;262(4 Pt 1):C876-81. PubMed.
  5. Lin SL, Kisseleva T, Brenner DA, Duffield JS. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol. 2008 Dec;173(6):1617-27. PubMed.
  6. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010 Jan;176(1):85-97. PubMed.
  7. Sundberg C, Ivarsson M, Gerdin B, Rubin K. Pericytes as collagen-producing cells in excessive dermal scarring. Lab Invest. 1996 Feb;74(2):452-66. PubMed.
  8. Meletis K, Barnabé-Heider F, Carlén M, Evergren E, Tomilin N, Shupliakov O, Frisén J. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol. 2008 Jul 22;6(7):e182. PubMed.
  9. Barnabé-Heider F, Göritz C, Sabelström H, Takebayashi H, Pfrieger FW, Meletis K, Frisén J. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell. 2010 Oct 8;7(4):470-82. PubMed.
  10. Dore-Duffy P, Balabanov R, Beaumont T, Hritz MA, Harik SI, Lamanna JC. Endothelial activation following prolonged hypobaric hypoxia. Microvasc Res. 1999 Mar;57(2):75-85. PubMed.
  11. Takahashi A, Park HK, Melgar MA, Alcocer L, Pinto J, Lenzi T, Diaz FG, Rafols JA. Cerebral cortex blood flow and vascular smooth muscle contractility in a rat model of ischemia: a correlative laser Doppler flowmetric and scanning electron microscopic study. Acta Neuropathol. 1997 Apr;93(4):354-68. PubMed.
  12. Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000 Jul;60(1):55-69. PubMed.
  13. Dore-Duffy P, Lamanna JC. Physiologic angiodynamics in the brain. Antioxid Redox Signal. 2007 Sep;9(9):1363-71. PubMed.

Further Reading

Papers

  1. Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med. 2005 May;11(5):572-7. PubMed.
  2. Kadoya K, Tsukada S, Lu P, Coppola G, Geschwind D, Filbin MT, Blesch A, Tuszynski MH. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron. 2009 Oct 29;64(2):165-72. PubMed.
  3. Hannila SS, Filbin MT. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp Neurol. 2008 Feb;209(2):321-32. PubMed.
  4. Alto LT, Havton LA, Conner JM, Hollis Ii ER, Blesch A, Tuszynski MH. Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat Neurosci. 2009 Sep;12(9):1106-13. PubMed.
  5. Nilsson M, Pekny M. Enriched environment and astrocytes in central nervous system regeneration. J Rehabil Med. 2007 May;39(5):345-52. PubMed.

Primary Papers

  1. Göritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisén J. A pericyte origin of spinal cord scar tissue. Science. 2011 Jul 8;333(6039):238-42. PubMed.

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