Human Muse Cells, Nontumorigenic Phiripotent-Like Stem Cells, Have Liver Regeneration Capacity through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis

Abstract

Muse cells, a novel type of nontumorigenic pluripotent-like stem cells, reside in the bone marrow, skin, and adipose tissue and are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-derived Muse cells to repair an immunodeficient mouse model of liver fibrosis was evaluated in this study. The cells exhibited the ability to spontaneously differentiate into hepatoblast/hepatocyte lineage cells in vitro. They demonstrated a high migration capacity toward the serum and liver section of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated in the liver, but not in other organs except, to a lesser extent, in the lungs at 2 weeks after intravenous injection in the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1 ± 15.2%), human albumin (54.3 ± 8.2%), and anti-trypsin (47.9 ± 4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human CYP1A2 and human Glc-6-Pase at 8 weeks after injection. Recovery in serum, total bilirubin, and albumin and significant attenuation of fibrosis were recognized with statistical differences between the Muse cell-transplanted group and the control groups, which received the vehicle or the same number of a non-Muse cell population of MSCs (MSCs in which Muse cells were eliminated). Thus, unlike ESCs and iPSCs, Muse cells are unique in their efficient migration and integration into the damaged liver after intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They may repair liver fibrosis by two simple steps: expansion after collection from the bone marrow and intravenous injection. A therapeutic strategy such as this is feasible and may provide significant advancements toward liver regeneration in patients with liver disease.

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

“…The SDF-1-CXCR4 axis may also be a candidate factor that triggers Muse cell mobilization. However, it has been already reported that CXCR4 antagonist AMD3100 in animal serum could only partially suppress Muse cell migration towards the damaged liver, and its suppression effect did not differ significantly between Muse and non-Muse cells, 15 suggesting that the effect of SDF-1 on mobilizing Muse cells is smaller than that of S1P.…”

Multilineage-differentiating stress-enduring (Muse)-like cells exist in synovial tissue

“…Muse cells were originally identified as cells that are resistant to long-term trypsin incubation and are known as cells that are double positive for the pluripotent surface marker, stage-specific embryonic antigen-3 (SSEA-3), and CD105, and that have the capacity for self-renewal and triploblastic differentiation from a single cell [6]. The applicability of Muse cells for regenerative treatments has been suggested in disease models of liver damage, stroke, skin ulcers related to diabetes mellitus, and osteochondral defects [9], [10], [11], [12].…”

Muse Cells: Nontumorigenic Pluripotent Stem Cells Present in Adult Tissues—A Paradigm Shift in Tissue Regeneration and Evolution

“…Muse cells also harbor the ability to home into the liver in a fulminant hepatitis mouse model replenishing new cells and contributing to tissue repair [8]. Muse cells migrate and integrate into damaged liver in a liver fibrosis mouse model [16]. Fibrotic liver area and serum total bilirubin are decreased, while serum total albumin is increased, demonstrating functional restoration [16].…”

“…They exist normally in a quiescent state and are activated when exposed to conditions of severe cellular stress both in vitro and in vivo [5, 7–9, 14]. In contrast to ESCs and iPSCs, Muse cells exhibit telomerase activity and asymmetric growth and thus do not undergo tumorigenesis or teratoma formation when transplanted into a host organism (Figures 2(a), 2(b), 2(d), and 2(e)) [5, 7–9, 14–16]. Muse cells also exhibit a normal karyotype, as they demonstrate normal chromosome number and integrity (Figure 2(i)).…”

“…They migrate to and integrate into damaged tissues to replenish cells and restore tissue function with high efficiency by single intravenous injection, as demonstrated in different animal disease models (e.g., fulminant hepatitis, muscle degeneration, skin ulcers, and brain stroke) [8–10, 16–18]. …”