Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex

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http://hdl.handle.net/10138/308139

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Nathan , K , Lu , L Y , Lin , T , Pajarinen , J , Jämsen , E , Huang , J-F , Romero-Lopez , M , Maruyama , M , Kohno , Y , Yao , Z & Goodman , S B 2019 , ' Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex ' , Bone & Joint Research , vol. 8 , no. 10 , pp. 481-488 . https://doi.org/10.1302/2046-3758.810.BJR-2018-0231.R2

Title: Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex
Author: Nathan, K.; Lu, L. Y.; Lin, T.; Pajarinen, J.; Jämsen, E.; Huang, J-F; Romero-Lopez, M.; Maruyama, M.; Kohno, Y.; Yao, Z.; Goodman, S. B.
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
Date: 2019-10
Language: eng
Number of pages: 8
Belongs to series: Bone & Joint Research
ISSN: 2046-3758
URI: http://hdl.handle.net/10138/308139
Abstract: Objectives Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures. Methods A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion. Results We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis. Conclusion These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.
Subject: Macrophages
Mesenchymal stem cells
Coculture
Osteogenesis
Sex differences
ALKALINE-PHOSPHATASE
STEROID REGULATION
SKELETAL-MUSCLE
BONE-MARROW
FRACTURE
GENDER
POLARIZATION
GROWTH
DIFFERENTIATION
PREVALENCE
1182 Biochemistry, cell and molecular biology
3126 Surgery, anesthesiology, intensive care, radiology
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