Pluripotent nontumorigenic multilineage differentiating stress enduring cells (Muse cells): a seven-year retrospective

Abstract

Multilineage differentiating stress enduring (Muse) cells, discovered in the spring of 2010 at Tohoku University in Sendai, Japan, were quickly recognized by scientists as a possible source of pluripotent cells naturally present within mesenchymal tissues. Muse cells normally exist in a quiescent state, singularly activated by severe cellular stress in vitro and in vivo. Muse cells have the capacity for self-renewal while maintaining pluripotent cell characteristics indicated by the expression of pluripotent stem cell markers. Muse cells differentiate into cells representative of all three germ cell layers both spontaneously and under media-specific induction. In contrast to embryonic stem and induced pluripotent stem cells, Muse cells exhibit low telomerase activity, a normal karyotype, and do not undergo tumorigenesis once implanted in SCID mice. Muse cells efficiently home into damaged tissues and differentiate into specific cells leading to tissue regeneration and functional recovery as described in different animal disease models (i.e., fulminant hepatitis, muscle degeneration, skin ulcers, liver cirrhosis, cerebral stroke, vitiligo, and focal segmental glomerulosclerosis). Circulating Muse cells have been detected in peripheral blood, with higher levels present in stroke patients during the acute phase. Furthermore, Muse cells have inherent immunomodulatory properties, which could contribute to tissue generation and functional repair in vivo. Genetic studies in Muse cells indicate a highly conserved cellular mechanism as seen in more primitive organisms (yeast, Saccharomyces cerevisiae, Caenorhabditis elegans, chlamydomonas, Torpedo californica, drosophila, etc.) in response to cellular stress and acute injury. This review details the molecular and cellular properties of Muse cells as well as their capacity for tissue repair and functional recovery, highlighting their potential for clinical application in regenerative medicine.

Keywords: Adult pluripotent stem cells; Cellular stress; High homing capacity; Muse cells; Nontumorigenic; Quiescence; Regenerative medicine.

Fig. 1

a Schematic of Muse-AT cell generation from lipoaspirate material. Different cellular components are present in adipose tissue (i.e., adipocytes, endothelial cells (ECs), adipose stem cells (ASCs), adipose tissue macrophages, and Muse-AT cells). Adipose tissue (lipoaspirate material) first exposed to collagenase for 30 minutes at 37 °C, and then for 12 hours under severe cellular stress conditions (i.e., long-term collagenase incubation, lack of nutrients, low temperature, and hypoxia). Only a cluster of Muse-AT cells survived such stress. b Expression of pluripotent stem cell markers SSEA4, Oct-4, Sox-2, and TRA1-6 in Muse-AT cells. c Expression of CD markers in Muse cells indicating an immunophenotype. d Evidence of a normal karyotype in Muse cells. e Muse-AT cells do not form teratomas after 6-month implantation in testis (right) in comparison with control, sham-injected testis (left). Muse-AT adipose tissue-derived multilineage differentiating stress enduring (c Reproduced from Figure 2 in Gimeno et al. [22] under CC-BY license) (d Reproduced from Figure 4 in Gimeno et al. [22] under CC-BY license) (e Reproduced from Figure 4 in Gimeno et al. [22] under CC-BY license)

Fig. 2

a TGF-β1 signaling blockade on IFN-γ secretion. Using a neutralizing monoclonal anti-TGF-β1, the inhibitory action on IFN-γ secretion was abolished in antigen (M)-specific stimulation of T cells. T cells were obtained from transgenic NOD BDC2.5 mice. Results representative of five separate experiments (Gimeno et al., unpublished data, 2017). b Putative intracellular signaling of TGF-β1 secreted by Muse-AT cells on T lymphocytes and macrophages. IFN-γ interferon gamma, IL interleukin, Muse-AT adipose tissue-derived multilineage differentiating stress enduring, TGF-β1 transforming growth factor-β1

Fig. 3

A Effect of Muse cells in damaged liver. Functional improvement shown in Muse cells by a decrease in bilirubin production, increase in albumin levels, and decrease in fibrotic tissues. B Effect of Muse cells in damaged kidney: (b₁) detection of GFP(+) Muse cells distributed in different tissues after 7 weeks of injection in FSGS-SCID mice; (b₂, b₃) Muse cells show significant decrease in glomerular sclerosis as well as fibrotic areas. C Effect of Muse cells in damaged neural tissue: (c₁) ipsilateral sensory cortex analysis in cerebral stroke-SCID mice after 84 days of Muse, non-Muse, and vehicle treatment; somatosensory evoked potentials show no effect in latency (c₂) and significant increase in amplitude (c₃) between Muse cells and vehicle controls; (c₄) integration of GFP(+) Muse cells into neural tissue at days 3 and 7 display neurite-like cell formation. D Effect of Muse cells in diabetic skin ulcers: (d₁) Muse-rich fraction shows significant reduction in percent wounded area in comparison with Muse-poor fraction at 14 days post implantation; (d₂) Muse-rich fraction expresses PECAM-1 and isolectin (markers of dermis and vascular endothelial cells) in upper dermis at 14 days post implantation; (d₃) Muse cells show negative expression of PECAM-1 and isolectin in middle and lower dermis 14 days post implantation. Muse multilineage differentiating stress enduring, ns not significant (A Reproduced with permission from Figure 4 in Iseki et al. [26]) (b₁ Reproduced with permission from Figure 2 in Uchida et al. [46], License Number 4141730401653) (b₂, b₃ Reproduced with permission from Figure 6 in Uchida et al. [46], License Number 4141730401653) (c₁–c₃ Reproduced from Figure 6 in Uchida et al. [23] under CC-BY license) (c₄ Reproduced from Figure 7 in Uchida et al. [23] under CC-BY license) (d₁ Reproduced with permission from Figure 5 in Kinoshita et al. [21], License Number 4136900281603) (d₂, d₃ Reproduced with permission from Figure 7 in Kinoshita et al. [21], License Number 4136900281603)