Transplantation of Unique, Newly Discovered Stem Cells May Lead to Promising Stroke Therapy


Stroke treatments have seen some remarkable advances in the past few years. Stem cell treatments for stroke have even seen some successes in clinical trials, showing that stem cell transplantation aimed at neural repair after a stroke is a possible way to ameliorate the effects of stroke.

Now, collaboration between teams of American and Japanese researchers has shown that a newly-identified stem cell has the ability to successfully treat stroke in rats. When administered to rats who have suffered from an experimentally-induced stroke, MUSE or multilineage-differentiating stress-enduring cells induced the regeneration of neurons and resulted in “significant improvements in neurological and motor functions” compared to control groups that were not transplanted with MUSE cells. MUSE cells also do not cause tumors.

The study has increased the number of therapeutic arrows in the quiver of neurologists and neuroscientists and lengthens the list of cells that might one day be considered for human clinical trials if continued pre-clinical tests prove successful. Future clinical studies aimed at regenerating neurological and motor function in patients who have suffered ischemic stroke.

The paper describing this study appeared in a recent issue of Stem Cells (Sept. 2015).

“Muse cells are unique stem cells that are able to self-renew and display high-efficiency for differentiating into neuron-like cells,” explained lead author Dr. Cesar V Borlongan, Distinguished Professor and Vice-Chairman for Research at the University of South Florida (USF) College of Medicine Department of Neurosurgery and Brain Repair and Director of USF’s the Center of Excellence for Aging and Brain Repair. “Unlike mesenchymal stem cells (MSCs) that have previously been used in stem cell transplantation in stroke-related clinical trials, in the present study Muse cells were found to possess functional characteristics of neurons as they attain the attributes of the host microenvironment. When MUSEcells were transplanted into to the brains of rats modeled with stroke, they attained neuronal characteristics.”

MUSE cells are found in many different tissues, including bone marrow, skin and fat. Since these cells can be derived from dermal fibroblasts (a type of connective tissue cell that provides the structural framework for animal tissues and plays a critical role in wound healing), they can be accessed with relative ease, without the need for the painful, invasive procedures required for obtaining other kinds of stem cells. Furthermore, while some stem cells used in stem cell transplantation studies have been found to cause cancer, MUSE cells do not produce tumors and exhibit exceptional tissue repair potential when introduced into the blood stream.

Some researchers think that fetal stem cells might be better candidates for replacing lost neural circuitry. The main reason in favor of fetal stem cells is that they preferentially differentiate into neuronal cells. However, the accessibility to fetal stem cells is limited and, like embryonic stem cells, the immaturity of these cells may present safety issues, such as tumor development. Additionally, the use of fetal and embryonic stem cells has many ethical difficulties to say the least. Since MUSE cells can be derived from adult tissue rather than fetal or embryonic tissue, the ethical quandaries associated with using them is minimal.

Not only do MUSE cells also have the practical advantage of being non-tumorigenic, they are readily accessed commercially and can also be easily collected from patient skin biopsies. MUSE cells also do not have to be “induced,” or genetically manipulated in order to be used, since they already display inherent stem cell properties after isolation. MUSE cells also spontaneously home toward the stroke-damaged sites.

“Ours is the first study to show that human skin fibroblast-derived Muse cells can have neuron-like function, possess an inherent ability to assume ‘stemness’ properties, and to readily differentiate into neural-lineage cells after integration into the stroke brain,” said co-lead author Dr. Mari Dezawa, Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine in Sendai, Japan. “Our results show that Muse cells are a feasible and promising source for cell-based approaches to ischemic stroke therapy.”

Human Fat Contains Multilineage Differentiating Stress Enduring Cells With Great Potential for Regenerative Medicine


A collaboration between American and Japanese scientists has discovered and characterized a new stem cell population from human fat that do not cause tumors and can differentiate into derivatives from ectoderm, mesoderm, and endoderm.

Multilineage Differentiating Stress-Enduring or Muse cells are found in bone marrow and the lower layers of the skin (dermis). Muse cells are a subpopulation of mesenchymal stem cells, and even express a few mesenchymal stem cell-specific genes (e.g., CD105, a cell-surface protein specific to mesenchymal stem cells). However, Muse cells also express cell surface proteins normally found in embryonic stem cells (e.g., stage-specific embryonic antigen-3, SSEA-3). Additionally, Muse cells have the ability to self-renew, and differentiate into cell types from all three embryonic germ layers, ectoderm (which forms skin and brain), mesoderm, (which forms muscle, bone, kidneys, gonads, heart, blood vessels, adrenal glands, and connective tissue), and endoderm (which forms the gastrointestinal tract and its associated tissues). Finally, Muse cells can home to damaged sites and spontaneously differentiate into tissue-specific cells as dictated by the microenvironment in which the cells find themselves.

A new publication by Fumitaka Ogura and others from Tohoku University Graduate School of Medicine in Sendai, Japan and Saleh Heneidi from the Medical College of Georgia (Augusta, Georgia), and Gregorio Chazenbalk from the David Geffen School of Medicine at UCLA has shown that Muse cells also exist in human fat.

The source of cells came from two places: commercially available fat tissue and freshly collected fat from human subjects, collected by means of liposuction. After growing these cells in culture, the mesenchymal stem cells and Muse cells grew steadily over the 3 weeks. Then the Dezawa research group used fluorescence-activated cell sorting (FACS) to isolate from all these cells those cells that express SSEA-3 on their cell surfaces.

FACS uses antibodies conjugated to dyes that can bind to specific cell proteins. Once the antibodies bind to cells, the cells are sluiced through a small orifice while they are illuminated by the laser. The laser activates the dyes if the cell fluoresces, one door opens and the other closes. The cell goes to one test tube. If the cell does not fluoresce, then the door stay shut and another door opens and the cell goes into a different test tube.  In this way, cells with a particular cell-surface protein are isolated from other cells that do not have that cell-surface protein.

Fluorescent-Activated Cell Sorting
Fluorescent-Activated Cell Sorting

In addition to expression SSEA-3, the fat-based Muse cells expressed other mesenchymal stem cell-specific cell-surface proteins (CD29, CD90), but they did not express proteins usually thought to be diagnostic for fat-based mesenchymal stem cells (MSCs) such as CD34 and CD146.  Muse cells also expressed pluripotency genes (Nanog, Oct3/4, PAR4, Sox2, and Tra-1-81).  The Muse cells grew in small clusters and some cell expressed ectodermal-specific genes (neurofilament, MAP2), others expressed mesodermal-specific genes (smooth muscle actin, NKX2) and endodermal-specific genes (alpha-fetoprotein, GATA6).  These data suggested that the cultured Muse cells were poised to form either ectoderm, mesodermal, or endodermal derivatives.

When transplanted into mice with non-functional immune systems, the Muse cells never formed any tumors or disrupted the normal structure of the nearly tissues.  When placed in differentiating media, fat-derived Muse cells differentiated into cells with neuron-like morphology that expressed neuron-specific genes (Tuj-1), liver cells, and fat.  When compared with Muse cells from bone marrow or skin, the fat-derived Muse cells were better at making bone, fat, and muscle, but not as good as bone marrow Muse cells at making neuronal cell types, but not as good at making glial cells.  Many of these assays were based on gene expression experiments and not more rigorous tests.  Therefore, the results of these experiments might be doubtful until they are corroborated by more rigorous experiments.

These cells are expandable and apparently rather safe to use.  More work needs to be done in order to fully understand the full regenerative capacity of these cells and protocols for handling them must also be developed.  However, hopefully pre-clinical experiments in rodents will give way to larger animal experiments.  If these are successful, then maybe human trials come next.  Here’s to hoping.