To scar or not to scar : origin and function of fibrotic tissue in the central nervous system
After injury, the adult mammalian central nervous system lacks long-distance axon regeneration, and insufficient repair results in the formation of a multicellular and compartmentalized scar. A great body of work has been dedicated to the study of the glial component of the scar, while the fibrotic lesion core has received less attention. This thesis aims to deepen our knowledge on the cellular origin and function of fibrotic scar tissue following central nervous system injury and disease.
In Paper I we revealed that a subset of perivascular cells lining the vasculature, termed type A pericytes, is the major source of stromal fibroblasts that constitute the extracellular matrixrich fibrotic component of the central nervous system scar following spinal cord injury in the mouse. Maximal genetic inhibition of proliferation by type A pericytes largely abolished fibrotic scar tissue generation and resulted in unsealed lesions and impaired wound healing, highlighting the importance of pericyte-derived scarring in regaining tissue integrity and wound closure. On the other hand, moderate inhibition of type A pericyte proliferation preserved wound closure and resulted in attenuated fibrotic scar tissue generation. This represented an attractive scenario to investigate the role of pericyte-derived scarring in axonal regeneration and functional recovery after spinal cord injury. In Paper II we demonstrated that attenuation of pericyte-derived scarring is accompanied by decreased fibrosis, extracellular matrix deposition, astrogliosis and inflammation, and promoted regeneration of raphespinal and corticospinal tract axons caudal to the lesion. Corticospinal tract axons found below the injury site established functional synapses with local spinal neurons. Recovery of sensorimotor function was improved in animals with reduced pericyte-derived scarring. These results established pericyte-derived scarring as a therapeutic target to improve recovery following central nervous system injury. In Paper III we asked whether generation of periycte-derived scar tissue is preserved across diverse central nervous system lesions. In addition to traumatic spinal cord injury, we found that type A pericyte progeny detached from the vascular wall and generated fibrotic scar tissue, or contributed to tumor stroma, after traumatic brain injury, inflammatory demyelinating disease and in a glioblastoma tumor model, respectively. Following cerebral ischemic stroke, type A pericytes increased in number but remained associated with the vasculature. We found that humans also develop fibrotic tissue enriched in stromal fibroblasts after central nervous system lesions, such as spinal cord injury and multiple sclerosis. In Paper IV we showed that lesions to the spinal cord white matter trigger greater pericytederived fibrotic scarring compared to grey matter lesions. We demonstrated that myelin damage, myelin itself and myelin-associated proteins function as potent inducers of pericytederived fibrotic scarring, a process that is temporally synchronized with and dependent on the infiltration of peripherally derived macrophages. Reduction of monocyte-derived macrophage infiltration into the injured central nervous system or deletion of MAG, OMgp and Nogo, well-known myelin-associated axon growth inhibitors, resulted in attenuated fibrotic scar tissue generation following spinal cord injury.
The work presented in this thesis collectively supports a role for pericytes in fibrotic scar tissue formation and fibrosis following central nervous system injury. Interfering with pericyte-derived scarring may represent a promising therapeutic strategy to facilitate recovery following central nervous system injury and disease.
List of scientific papers
I. Christian Göritz, David O. Dias, Nikolay Tomilin, Mariano Barbacid, Oleg Shupliakov and Jonas Frisén. (2011). A Pericyte Origin of Spinal Cord Scar Tissue. Science. 333:238-242.
https://doi.org/10.1126/science.1203165
II. David O. Dias, Hoseok Kim, Daniel Holl, Beata W. Solnestam, Joakim Lundeberg, Marie Carlén, Christian Göritz† and Jonas Frisén†. (2018). Reducing Pericyte-derived Scarring Promotes Recovery after Spinal Cord Injury. Cell. 173:153-165. †Co-corresponding authors.
https://doi.org/10.1016/j.cell.2018.02.004
III. David O. Dias*, Jannis Kalkitas*, Yildiz Kelahmetoglu*, Cynthia P. Estrada, Jemal Tatarishvili, Aurélie Ernst, Hagen B. Huttner, Zaal Kokaia, Olle Lindvall, Lou Brundin, Jonas Frisén and Christian Göritz. A Pericyte Origin of Fibrotic Scar Tissue Across Diverse Central Nervous System Lesions. *These authors contributed equally. [Manuscript]
IV. Jannis Kalkitsas*, David O. Dias*, Francesco Boato, Maria Kovatchka, Yutong Feng, Jian Zhong and Christian Göritz. The myelin components Nogo, OMgp and MAG induce fibrosis after CNS injury. *These authors contributed equally. [Manuscript]
History
Defence date
2019-12-13Department
- Department of Cell and Molecular Biology
Publisher/Institution
Karolinska InstitutetMain supervisor
Göritz, ChristianCo-supervisors
Frisén, JonasPublication year
2019Thesis type
- Doctoral thesis
ISBN
978-91-7831-638-0Number of supporting papers
4Language
- eng