Organ transplantation remains the only treatment for patients with advanced liver injury. Globally, the limited number of donors fails to meet the demand, making it necessary to develop alternative therapies. Bone marrow-derived macrophages (BMDMs) stimulate the proliferation of hepatocyte progenitors and reduce hepatic fibrosis in mouse models of liver damage. Thus, macrophages appear a valuable option to efficient liver repair therapies.
Pointing to future clinical settings, Haiseri and coworkers recently established a protocol for the generation of macrophages from mouse embryonic stem cells (ESCs) in vitro, at large scale. Briefly, ESCs grown in the presence of CSF-1 and IL-3 form embryoid bodies, which adhere to tissue culture plastic and release non-adherent macrophage progenitor cells into the medium. When treated with CSF-1 alone, the harvested progenitor cells give rise to a monolayer of embryonic stem cell derived macrophages (ESDMs), morphologically similar to BMDMs yet less inflammatory.
When administered to a murine, carbon tetrachloride-induced injury and fibrosis model, ESDMs elicited proliferation of hepatic progenitor cells and downregulated the number of fibrogenic myofibroblasts, reducing the amount of hepatic fibrosis to 50% of controls.
Ten-fold higher doses of ESDMs were required to achieve therapeutic effects similar to those obtained with BMDMs. However, ESDMs repopulated the Kupffer cell compartment of macrophage-depleted livers more efficiently than BMDMs, suggesting that ESDMs have a phenotype more akin to tissue resident macrophages. Further, they significantly improved the function of liposomal clodronate-damaged livers, evidenced by albumin and alkaline phosphatase serum levels lowered to those of healthy controls.
This work demonstrates that macrophages derived from ESCs are functionally therapeutic for chronic liver disease, both by reducing fibrosis and by stimulating liver regeneration.
The article, titled “Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury,” was published in npj Regenerative Medicine.