AsianScientist (May 26, 2015) – A study published in Cell Research as the cover story has identified the four cytokines required for the long-term maintenance of muscle stem cells in vitro: IL-1α, IL-13, TNF-α, and IFN-γ.
Adult stem cells have long been considered as a very promising candidate cell source for regenerative medicine. They are non-tumorigenic, relatively safe, and less controversial than embryo manipulation.
The ideal strategy of adult cell therapy would start with taking a small biopsy from the patient or donor. The stem cells will then be isolated and expanded in vitro to yield a sufficient amount of cells for transplantation.
However, this strategy has been hampered by the lack of an efficient in vitro system to expand functional adult stem cells. The majority of the adult stem cells, including hematopoietic stem cells and muscle stem cells (MuSCs), are unable to be expanded in vitro.
In particular, MuSCs can barely be cultured and expanded in vitro, while ex vivo cultured MuSCs differentiate to myoblast progenitor cells in a few days and lose most of their abilities to regenerate new muscles in vivo. Because of these difficulties, initial clinical trials of myoblast progenitor transplantation have failed. Establishment of an in vitro system to culture and expand functional MuSCs would help break this bottleneck and pave the way for adult stem cell-based therapies.
In the present study, Professor Hu Ping and Professor Wang Hongyan’s research groups from Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, solved the in vitro MuSCs expansion problem. They started their investigation by characterizing the endogenous microenvironment of MuSCs proliferation and expansion.
Firstly, they identified T cells as a critical MuSCs microenvironment component, showing that MuSCs proliferation was greatly promoted by co-culturing with T cells. By mimicking the endogenous microenvironment in vitro, functional MuSCs could be expanded for over 20 passages in vitro.
In a collaborative investigation, Hu and Wang’s groups further nailed the minimum effective components of cytokines secreted by T cells down to just four cytokines: IL-1α, IL-13, TNF-α, and IFN-γ. MuSCs cultured in medium supplemented with the four cytokines maintained their stemness for over 20 passages. The starting number of MuSCs was increased for over 1018 fold in this in vitro expansion system.
The in vitro expanded MuSCs express all the MuSCs markers and were able to repair muscle injury in vivo efficiently. The transplanted MuSCs were capable of homing to the right niche and replenishing the endogenous MuSCs pool. The authors were also able to show that the exogenous MuSCs are able to repair multiple rounds of muscle injuries after a single implantation.
These results showed that T cell-mediated acute inflammation provides an indispensable microenvironment for MuSCs expansion. It may provide new guidance for the usage of anti-inflammation drugs after trauma.
Furthermore, the establishment of the in vitro system to expand functional MuSCs for long term can provide sufficient amount of MuSCs for potential regenerative medicine. These findings represent a significant advancement towards treating muscle atrophy and injuries by MuSCs based therapy. It also provides new strategies to expand other types of adult stem cells in vitro.
The article can be found at: Fu et al. (2015) Combination Of Inflammation-related Cytokines Promotes Long-term Muscle Stem Cell Expansion.
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Source: Chinese Academy of Science.
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