Discovery of Multilineage-Differentiating Stress-Enduring (Muse) Stem Cells
We discovered a new type of pluripotent stem cells in adult human mesenchymal tissue, and termed them "multilineage-differentiating stress-enduring (Muse)" cells (Kuroda et al., 2010, PNAS；Wakao et al., 2011, PNAS; Kuroda et al., Nature Protocol, 2013). These cells were found to:
- Exist in bone marrow, skin, adipose, and other mesenchymal tissues, as well as in the connective tissues of many organs.
- Be present in commercially available mesenchymal cell cultures, which ensure their easy availability and accessibility.
- Be capable of differentiating into various types of somatic cells.
- Have the potential to self-renew.
- Present a very low risk of tumorigenicity, because they are naturally occurring cells.
- Be present in bone marrow and mesenchymal stem-cell transplants at 0.03% and ca. 1%, respectively; these facts warrant their safety.
- Proliferate at a rate similar to fibroblasts.
Somatic or tissue stem cells generally differentiate into cells that constitute the tissue in which they are found. For example, neural stem cells generate neuronal and glial cells, and hematopoietic stem cells produce various types of blood cells. However, mesenchymal stem cells can differentiate into extramesenchymal lineages such as neural (ectoderm) and hepatic (endoderm) cells, as well as into cell types found in tissues of mesenchymal origin such as bone, cartilage, and adipose. These findings gave rise to the idea that at least a subset of mesenchymal stem cells may be pluripotent. Mesenchymal stem cells are heterogeneous and harvested as a crude population of adherent cells. The identification of pluripotent stem cells, possibly present at a very low frequency in mesenchymal tissue, may be quite difficult.
Our laboratory has successfully isolated Muse cells from adult human skin, bone marrow, and other mesenchymal tissues. Muse cells are capable of differentiating into endodermal, mesodermal, and ectodermal cells from a single cell. They are characterized by stress resistance, self-renewal, and expression of pluripotent stem-cell markers. One of the major advantages of these endogenous cells is their non-tumorigenic properties. Muse cells are positive for both the mesenchymal marker CD105 and the human embryonic stem (ES) cell marker SSEA-3, and these markers are used to isolate them from mesenchymal cell cultures.
Due to their pluripotency and lack of tumorigenic potential, Muse cells are expected to have a promising future in regenerative medicine. Their most important advantage is that:
- Muse cells readily integrate into injured sites and mediate tissue repair via tissue-specific differentiation when administered in vivo.
Stated differently, Muse cells are extremely useful and convenient tissue regenerators because they
- Lack tumorigenic properties, and
- Do not require artificial differentiation or induction.
Clinical applications of ES cells and induced pluripotent stem (iPS) cells must overcome two major hurdles: successful differentiation into the target cell type, and elimination of undifferentiated cells with tumorigenic potential. By contrast, Muse cells administered in vivo will recognize and integrate into damaged sites and start to differentiate into cells that match the tissue. Therefore, Muse cells do not necessarily require maneuvers, aimed at inducing differentiation, at a cell-processing center. Mesenchymal stems cells, from which Muse cells are collected, have been used in a large number of clinical studies around the world. The results of these studies suggest the safety of the Muse cell-based approach. These advantages make Muse cells practical and plausible candidates for regenerative medicine.
Basic research currently conducted in our laboratory includes the following topics:
- Developmental origin of Muse cells
- Factors regulating in vivo functions and kinetics of Muse cells
- MicroRNA regulation of Muse cell differentiation
- Factors controlling Muse cell proliferation
- Comparative analysis of Muse cells harvested from different tissues
In addition, we are conducting studies in cooperation with many national and international research organizations to promote regenerative medicine for treatment of the following conditions:
- Cardiac diseases
- Hepatic diseases
- Cerebral infraction, nerve injury, neurodegenerative diseases
- Renal failure
- Diabetes mellitus
- Skin disorders
- Sensory impairment
- Bone and cartilage disorders
We are recruiting researchers and students who are interested in regeneration science and its clinical applications to join our projects.
Professor and Chair, Division of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine
2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575
E-mail: mdezawa*med.tohoku.ac.jp (This e-mail address has been disguised to avoid spam. Please amend it by replacing the asterisk [*] with ‘@.’)