A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components

Abstract

Genotyping graft livers by short tandem repeats after human living-donor liver transplantation (n ¼ 20) revealed the presence of recipient or chimeric genotype cases in hepatocytes (6 of 17, 35.3%), sinusoidal cells (18 of 18, 100%), cholangiocytes (15 of 17, 88.2%) and cells in the periportal areas (7 of 8, 87.5%), suggesting extrahepatic cell involvement in liver regeneration. Regarding extrahepatic origin, bone marrow mesenchymal stem cells (BM-MSCs) have been suggested to contribute to liver regeneration but compose a heterogeneous population. We focused on a more specific subpopulation (1-2% of BM-MSCs), called multilineage-differentiating stress-enduring (Muse) cells, for their ability to differentiate into liver-lineage cells and repair tissue. We generated a physical partial hepatectomy model in immunodeficient mice and injected green fluorescent protein (GFP)-labeled human BM-MSC Muse cells intravenously (n ¼ 20). Immunohistochemistry, fluorescence in situ hybridization and species-specific polymerase chain reaction revealed that they integrated into regenerating areas and expressed liver progenitor markers during the early phase and then differentiated spontaneously into major liver components, including hepatocytes (%74.3% of GFP-positive integrated Muse cells), cholangiocytes (%17.7%), sinusoidal endothelial cells (%2.0%), and Kupffer cells (%6.0%). In contrast, the remaining cells in the BM-MSCs were not detected in the liver for up to 4 weeks. These results suggest that Muse cells are the predominant population of BMMSCs that are capable of replacing major liver components during liver regeneration.

Sinusoidal communication in liver fibrosis and regeneration

“…Recently, Katagiri and colleagues observed that a small representation (1–2%) of bone marrow mesenchymal stem cells, named Muse, differentiate into liver-lineage cells and repair tissue. After their infusion in a model of partial hepatectomy, they integrated into regenerating areas and expressed liver progenitor markers during the early phase of regeneration to then differentiate into hepatocytes, KC and LSEC [89]. Muse cells can be obtained easily from patients and donors, and could be used for clinical applications.…”

Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase

“…All statistical analyses were performed using StatView version 5.0 (SAS Institute Inc., Cary, NC, USA). 7 …”

Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model

“…The proportion of Muse cells in the BM-mononucleated cells is ~0.03%, so that ~30 ml bone marrow aspirate yields approximately 1 million Muse cells by ~3 days 11 . Intravenously injected naive Muse cells migrate to and integrate into damaged sites and spontaneously differentiate into functional cells in injury models of the liver, muscle and skin 11,14 . Grafted Muse cells contribute to tissue reconstruction in skin ulcers of a diabetes mellitus model by replenishing new dermal and epidermal cells; similarly human skin fibroblast-derived Muse cells rebuild pyramidal and sensory tracts by replacing new functional neuronal cells in the cortex that could extend neurites into the contralateral spinal cord and physiologically evoke firing potentials 15–17 .…”