THE ROLE OF MACROPHAGE IN CARTILAGE REGENERATION AND THERAPY DEVELOPMENT
Author(s)
Yang, Jiabei
Advisor(s)
Ge, Zigang
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Abstract
As an important component of microenvironment, macrophages have crucial regulatory functions in stem cell activities. The crosstalk between macrophage and stem cell is still elusive in the context of cartilage regeneration. Current understanding of macrophage functions on cartilage is mainly from arthritis studies. However, the role of macrophage in cartilage regeneration after osteochondral injury remains largely unexplored. This dissertation mainly focuses on the function of macrophage in cartilage regeneration after osteochondral injury, while its involvement in abnormal skeleton development is also discussed.
First, the role of native macrophage in self-regeneration of articular cartilage in juvenile mice was investigated. In CCR2 (C-C chemokine receptor type 2) inactivation mice, the landscape of macrophage activation and composition in the synovium was described. By clodronate liposome injection, joint macrophages were selectively depleted to investigate the influence on regeneration. And the mechanisms were explored. The study demonstrated the majority of macrophages after injury were differentiated from circulating monocytes in a CCR2-dependent manner. Macrophage depletion hampered cartilage regeneration, via reducing proliferation and increasing apoptosis at the defect.
Second the therapeutic potentials of exogeneous macrophages in osteochondral injury were investigated. Bone marrow macrophages were harvested and polarized into M1, M2a and M2c macrophages in vitro. They were injected into adult mice without regeneration capacity after osteochondral injury. The influence of administration time was also investigated. During this process, activation and distribution of stem cells were explored. It showed that macrophages could enhance regeneration of cartilage and subchondral bone in a time- and phenotype-dependent manner, providing a pro-regenerative microenvironment for activated stem cells.
Third, osteochondral injury and postnatal skeleton development in pathological conditions were investigated. Sickle cell disease is an autosomal recessive disease, casing blood disorder and abnormal vascular microenvironment. It further causes a series of cartilage and bone problems. Due to limited knowledge of cartilage regeneration and skeleton development under sickle cell disease, they were studied in this research, and macrophage as well as monocyte/macrophage-lineage-derived osteoclast were investigated during the process. By combining histology, cell culture, protein assay and immunohistochemistry methods, the study revealed that sickle cell disease altered the balance of cartilage and bone, resulting in failure of cartilage reconstruction and delayed postnatal development of femoral head.
In summary, this research provides the direct evidence for regulation of cartilage regeneration by macrophage in vivo after osteochondral injury. It also demonstrates the different functions of macrophage subsets in regeneration of osteochondral injury for the time, as well as the importance of time window. This research investigates osteochondral injury and delayed femoral head development in sickle cell disease. The significance of macrophage in regulating cartilage regeneration and postnatal development is highlighted in this dissertation, serving as the kick-starter to understand the complicated topic of immunity in cartilage regeneration niche and mechanisms of disease caused abnormal skeleton problems. Functional restoration of cartilage still remains a clinical challenge. Investigation of regulatory role of macrophage during cartilage regenerating process is important for understanding regeneration mechanisms and improving treatment.
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Date
2021-07-20
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Text
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Dissertation