Muse Stem Cells Explained: What Makes Them Different?

Not all stem cells are the same.

Within the broader world of mesenchymal stromal and stem cells, or MSCs, researchers have identified a particularly interesting population known as Muse cells.

Muse stands for multilineage-differentiating stress-enduring.

The name gives away one of the characteristics that first made these cells interesting to researchers: they appear unusually capable of surviving stressful biological conditions.

But what exactly makes a Muse cell different from another mesenchymal stem cell? Are Muse cells created through special culture conditions? Are they found in umbilical cord tissue? And what does current research actually show?

Here is what patients should know.

Quick Answer: What Are Muse Stem Cells?

Muse cells are a naturally occurring population of stress-tolerant cells that have been identified within mesenchymal tissues.

Researchers commonly characterize Muse cells by expression of a marker called SSEA-3, often alongside mesenchymal markers such as CD105.

Laboratory research has found that Muse cells can:

• Survive unusually stressful environments
• Self-renew
• Demonstrate multilineage differentiation under experimental conditions
• Participate in cellular signaling associated with damaged tissue
• Be identified within several different human tissues

Muse cells have been reported in bone marrow, connective tissue, skin, adipose tissue, peripheral blood, amniotic tissue, and human umbilical cord tissue. [1-4]

They are now being investigated in human clinical research involving conditions such as stroke, spinal cord injury, myocardial infarction, and neonatal hypoxic-ischemic encephalopathy. [5-7]

However, Muse cell therapy remains an emerging area of regenerative medicine research.

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Watch: Dr. John Dame and Dr. Rob Kellar Discuss Muse Stem Cells

Video Transcript

Dr. John Dame:
There’s a subclass called Muse stem cells. That’s one that’s kind of coming to light with more investigation, so can you speak a little bit more to Muse stem cells and how those play into the equation?

Dr. Rob Kellar:
For sure. Muse stem cells originated by a Japanese researcher who kind of discovered them and named them, and they’re really kind of like a super soldier.

So, you take a population of cells and you do the expansion process that we described, and you predetermine where your passage is going to cut off.

Let’s just say you’re going to use an umbilical cord Wharton’s jelly MSC, and you say, “We’re going to stay below passage ten.”

But for the ten passages, what we’re going to do is add another level of stress while we culture it.

One of the most common knobs that’s turned is we lower oxygen. So you grow them under hypoxic conditions. It’s like altitude training for a stem cell.

Dr. John Dame:
Yeah.

Dr. Rob Kellar:
So what ends up happening as you expand these is you keep the ones that survive, and your next generation is stronger than the prior generation.

They’re more robust. They’re more capable of handling stressful environments. They’re more likely to survive.

So that’s kind of the thinking behind it.

Transcript lightly edited for punctuation and readability without changing the speakers’ meaning.

Important Context About the Video

Dr. Kellar’s “altitude training” analogy is a helpful way to explain the broader concept of cellular stress conditioning, but there is an important scientific distinction.

Muse cells are not defined simply as MSCs that have been cultured under low-oxygen conditions.

Researchers originally identified Muse cells as a naturally occurring, stress-tolerant subpopulation within mesenchymal cell populations. They are typically characterized using biological markers, particularly SSEA-3. [1-3]

Stressful laboratory conditions can be used to select for or enrich stress-resistant cells, and hypoxic culture is also studied more broadly as a way of altering MSC behavior.

But:

Low oxygen + repeated passages does not automatically equal a Muse cell product.

If a product is specifically described as containing Muse cells, the final cell population should be appropriately characterized.

1. What Are Muse Stem Cells?

Muse cells were first identified by researchers in Japan while studying human mesenchymal cell populations.

Researchers noticed that a small group of cells could survive conditions that killed many of the surrounding cells.

Those surviving cells demonstrated several unusual characteristics.

In laboratory experiments, Muse cells have shown:

• Stress tolerance
• Self-renewal
• Expression of pluripotency-associated markers
• Differentiation into multiple cell lineages under experimental conditions
• Low tumorigenic potential compared with some other pluripotent cell types

The term Muse was eventually used to describe these:

Multilineage-Differentiating Stress-Enduring cells.

One important distinction is that these cells occur naturally.

They are not genetically reprogrammed in the same way as induced pluripotent stem cells, commonly called iPS cells.

2. Why Are They Called “Stress-Enduring”?

The “stress-enduring” part of the name is one of their defining characteristics.

During the original research, investigators subjected populations of mesenchymal cells to severe cellular stress.

Most cells could not tolerate the conditions.

A smaller population survived.

Researchers then studied those surviving cells and found that they had characteristics that distinguished them from much of the broader mesenchymal cell population. [1-3]

This stress resistance became particularly interesting because injured tissue can itself be a biologically stressful environment.

An injured area may involve:

• Inflammation
• Oxidative stress
• Reduced oxygen availability
• Cellular debris
• Immune activity
• Tissue damage

Researchers began asking whether a cell population capable of surviving those conditions might behave differently from other cells used in regenerative medicine.

3. Are Muse Cells Created Through Hypoxic Culture?

Not exactly.

This is where the distinction between selecting cells and creating a cell type becomes important.

Hypoxia means reduced oxygen.

Researchers frequently study MSCs under hypoxic conditions because oxygen concentration can influence:

• Cell metabolism
• Survival
• Proliferation
• Gene expression
• Cell signaling
• Stress resistance

This is the concept Dr. Kellar compares to altitude training in the video.

An athlete who trains at altitude is exposed to an environmental stress that causes physiological adaptation.

Researchers can similarly alter the environment in which cells are cultured.

However, Muse cells are not defined solely by being grown under hypoxia.

Muse cells exist as a specific population that can be identified using characteristics such as SSEA-3 expression.

Therefore:

Hypoxic preconditioning may influence a cell population, but it should not automatically be described as creating Muse cells.

4. Muse Cells vs Mesenchymal Stem Cells

Muse cells and mesenchymal stromal or stem cells are related, but the terms should not be used interchangeably.

Mesenchymal Stromal/Stem Cells

MSC populations are heterogeneous.

That means every cell within a population of MSCs is not necessarily identical.

MSCs are studied extensively for their potential roles involving:

• Cellular signaling
• Immune modulation
• Tissue support
• Inflammatory pathways
• Secretion of growth and signaling factors

Muse Cells

Muse cells appear to represent a more specific population found within certain mesenchymal tissues.

Researchers have described Muse cells as having characteristics including:

• SSEA-3 expression
• Significant stress tolerance
• Self-renewal
• Multilineage differentiation under experimental conditions
• Distinct migration behavior in preclinical models

This means a study involving a purified or characterized Muse cell population cannot automatically be used to describe every ordinary MSC preparation.

Likewise, research involving general MSCs is not automatically Muse cell research.

5. How Are Muse Cells Identified?

One of the best-known markers used in Muse cell research is:

SSEA-3

SSEA stands for stage-specific embryonic antigen-3.

Muse cells were originally isolated from mesenchymal cell populations using markers including SSEA-3 and CD105. [2]

Researchers may use laboratory techniques such as:

• Fluorescence-activated cell sorting
• Magnetic cell sorting
• Flow cytometry
• Cell-surface marker analysis
• Specific stress-selection methods

This is an important point when evaluating commercial stem cell products.

The words:

“umbilical cord stem cells”

do not tell you whether Muse cells have actually been identified in the final product.

That requires product-specific characterization.

6. Are Muse Cells Found in Umbilical Cord Tissue?

Yes.

This is where Muse research becomes particularly relevant to discussions about umbilical cord-derived MSCs.

Researchers have identified SSEA-3-positive Muse-like cells within human umbilical cord tissue.

A 2024 study specifically isolated and characterized SSEA-3-positive cells from human umbilical cord.

Researchers reported that these cells shared multiple characteristics associated with adult tissue-derived Muse cells, including:

• Expression of pluripotency-associated markers
• Multilineage differentiation under laboratory conditions
• Stress tolerance
• Migration behavior in experimental models
• Low telomerase activity
• Lack of tumor formation in the experimental models studied [4]

Research has also identified SSEA-3-positive populations within areas of the umbilical cord including Wharton’s jelly.

But There Is an Important Limitation

Finding Muse cells in umbilical cord tissue does not mean every umbilical cord-derived product contains the same number or type of Muse cells.

Processing can dramatically affect the final product.

Factors may include:

• How the tissue is collected
• How cells are isolated
• Culture conditions
• Passage number
• Oxygen conditions
• Storage
• Cryopreservation
• Thawing
• Final cell viability

So although umbilical cord tissue can contain Muse-like cells, that does not automatically make every umbilical cord MSC product a Muse stem cell product.

7. What Does “Homing” Mean?

One of the most interesting aspects of Muse cell research is a concept known as homing.

Homing refers to the ability of circulating cells to respond to biological signals associated with damaged tissue.

Researchers studying Muse cells have investigated a signaling pathway involving:

Sphingosine-1-phosphate, or S1P

and its receptor:

S1PR2

Damaged cells can release S1P.

Muse cells express S1PR2, and experimental research has suggested that this signaling relationship may contribute to migration toward damaged tissue.

This concept is particularly interesting because several experimental and clinical Muse cell studies have used intravenous administration.

However, this should not be simplified into:

“Every IV stem cell automatically finds every damaged part of your body.”

That claim goes far beyond what the research establishes.

Different cell populations behave differently, and findings involving a specifically characterized Muse cell product cannot automatically be applied to every IV MSC preparation.

8. Why Are Researchers Interested in Muse Cells?

Several characteristics make Muse cells scientifically interesting.

Stress Tolerance

Their ability to survive harsh cellular environments may potentially matter when considering damaged or inflamed tissue.

Multilineage Potential

Laboratory research has demonstrated differentiation into multiple cell types under experimental conditions.

Migration Toward Damage

Preclinical research suggests Muse cells may respond to molecular signals released following tissue injury.

Potential for IV Administration

Because of their proposed migration behavior, researchers have investigated systemic administration rather than requiring cells to be injected directly into every damaged organ.

Low Tumorigenic Potential

One major concern with certain pluripotent stem-cell types is unwanted tumor formation.

Muse cells have demonstrated lower tumorigenic behavior in experimental research compared with some other pluripotent cell types.

These characteristics explain why Muse cells have moved from laboratory research into early human clinical studies.

9. What Human Studies Have Been Done?

Muse cell research has progressed into human trials.

A clinical-grade allogeneic Muse cell product known as CL2020 has been investigated in several medical conditions.

Ischemic Stroke

Researchers conducted a randomized, double-blind, placebo-controlled trial using intravenous CL2020 in patients recovering from ischemic stroke.

The study included 35 patients.

Researchers reported encouraging differences in certain functional outcomes, although treatment-related adverse reactions were also observed.

The results were considered promising enough to support further investigation, but they do not establish Muse therapy as a universally effective stroke treatment. [5]

Cervical Spinal Cord Injury

A small multicenter clinical study evaluated intravenous Muse cells in patients with traumatic cervical spinal cord injury.

Researchers primarily examined safety and feasibility.

Functional and neurological improvements were observed, but because there was no control group, the study could not establish how much improvement resulted from the therapy versus natural recovery or other treatment. [6]

Neonatal Hypoxic-Ischemic Encephalopathy

Muse cells have also been investigated in infants with hypoxic-ischemic encephalopathy.

A small early-stage study evaluated Muse cells alongside therapeutic hypothermia.

Researchers reported acceptable tolerability in the small study but emphasized that larger controlled trials are necessary. [7]

Acute Myocardial Infarction

An early first-in-human study investigated Muse cells following acute myocardial infarction.

The initial study involved only three patients.

While researchers reported encouraging findings, a trial that small cannot determine whether the treatment is effective.

What Does This Mean?

Muse cells are a legitimate area of human clinical research.

That does not mean Muse cell therapy is established for every condition discussed in regenerative medicine.

Much of the research remains:

• Early-stage
• Small
• Condition-specific
• Product-specific

Those limitations matter.

10. Are Muse Cells FDA-Approved?

Muse cell therapy is not currently an FDA-approved regenerative treatment for orthopedic injuries or general wellness applications in the United States.

The U.S. Food and Drug Administration regulates human cells, tissues, and cellular and tissue-based products based on factors including how they are processed and how they are intended to be used.

The FDA has repeatedly cautioned consumers about unapproved regenerative medicine products marketed for conditions for which safety and effectiveness have not been established.

This includes products marketed using terms such as:

• Stem cells
• Umbilical cord products
• Wharton’s jelly
• Exosomes
• Other regenerative therapies

Research and FDA approval are not the same thing.

11. Does Every Umbilical Cord Product Contain Muse Cells?

No.

This is probably the most important practical takeaway from this article.

Research shows that Muse-like cells can exist in umbilical cord tissue.

But a specific commercial product may differ depending on:

• Tissue source
• Cell isolation
• Culture conditions
• Passage number
• Processing
• Storage
• Cryopreservation
• Viability
• Cell characterization

If a product is marketed specifically as containing Muse cells, patients should be able to ask:

• Was the final product tested for SSEA-3?
• What percentage of cells expressed that marker?
• Was testing performed before or after processing?
• Was cell viability measured?
• Which laboratory performed the testing?
• Is there documentation?
• Is the product similar to products used in published Muse research?

The newest scientific term should not be used as a marketing shortcut.

12. Questions Patients Should Ask About Muse Cells

If a clinic discusses Muse cells with you, consider asking:

Are you actually using a Muse cell product?

Ask whether Muse cells have been identified in the specific product being administered.

How were the cells characterized?

SSEA-3 testing is highly relevant to Muse cell identification.

Where do the cells come from?

Muse cells have been identified in multiple tissues, including umbilical cord, bone marrow, adipose tissue, and others.

What passage are the cells?

Passage refers to the number of times cells have been transferred and expanded during laboratory culture.

Passage number can influence cellular characteristics, although a specific passage number alone does not identify a Muse cell.

Were the cells grown under hypoxic conditions?

Hypoxic culture can alter MSC behavior and may be part of particular manufacturing or research strategies.

It is still different from proving that a final product contains Muse cells.

What research applies to this exact product?

This may be the most important question.

A study involving one carefully characterized Muse cell product should not automatically be used to claim that another umbilical cord-derived preparation will produce the same effects.

Frequently Asked Questions

What does MUSE stand for?

Muse stands for:

Multilineage-Differentiating Stress-Enduring

The name refers to the cells’ observed ability to tolerate significant cellular stress while demonstrating multilineage characteristics in laboratory research.

Who discovered Muse cells?

Muse cells were first characterized by researchers in Japan studying populations of human mesenchymal cells.

The research group led by Mari Dezawa at Tohoku University played a central role in their discovery and characterization. [1]

Are Muse cells just stronger stem cells?

“Stronger” is an easy way to explain their stress tolerance, but it is not a precise scientific definition.

Muse cells appear unusually resistant to cellular stress and demonstrate several biological characteristics that distinguish them from many other cells in heterogeneous MSC populations.

Are Muse cells created by hypoxia?

No.

Muse cells are considered a naturally occurring cell population.

Low-oxygen or other stressful culture conditions may influence or enrich certain stress-resistant cells, but growing MSCs under hypoxia alone does not automatically make them Muse cells.

Are Muse cells the same as MSCs?

Not exactly.

Muse cells can exist within broader mesenchymal stromal or stem cell populations, but they represent a more specifically characterized subpopulation.

Are Muse cells found in Wharton’s jelly?

Researchers have identified SSEA-3-positive Muse-like populations in human umbilical cord tissue, including research involving Wharton’s jelly-derived cells.

Do all umbilical cord stem cells contain Muse cells?

No.

Muse cells may represent only a subset of the cellular population.

A specific processed product would need appropriate testing to determine whether Muse cells remain present.

What is SSEA-3?

SSEA-3 stands for stage-specific embryonic antigen-3.

It is one of the primary cell-surface markers researchers use to identify Muse cells.

Can Muse cells find injured areas of the body?

Researchers have investigated Muse cell migration toward damaged tissue through signaling pathways involving S1P and S1PR2.

This is an active area of research.

It should not be interpreted as proof that every intravenously administered stem cell product automatically travels to and repairs damaged tissue.

Have Muse cells been tested in humans?

Yes.

Early human studies have investigated a specifically manufactured Muse cell product in conditions including:

• Ischemic stroke
• Cervical spinal cord injury
• Myocardial infarction
• Neonatal hypoxic-ischemic encephalopathy

These studies remain relatively early, and larger controlled trials are still needed.

Are Muse cells FDA-approved?

There is currently no FDA-approved Muse cell therapy for routine orthopedic or general regenerative medicine use in the United States.

Does The Re/ Clinic use Muse stem cells?

The Re/ Clinic uses regenerative biologic products involving umbilical cord-derived cells and tissue.

Research has shown that Muse-like populations can exist within umbilical cord tissue.

However, whether a specific final product contains Muse cells should depend on product-specific characterization rather than simply assuming all umbilical cord-derived MSC preparations contain them.

Patients are encouraged to ask our team about the sourcing, processing, testing, and characteristics of the particular biologic product being discussed.

Understanding Stem Cells Means Looking Beyond the Label

“Muse cells,” “mesenchymal stem cells,” and “umbilical cord stem cells” are related terms, but they are not interchangeable.

Muse research is exciting because it highlights just how biologically diverse stem cell populations can be.

It also demonstrates why patients should look beyond the words “stem cell therapy” and ask what type of cells are actually being discussed.

At The Re/ Clinic in Sandy, Utah, our medical team can discuss our regenerative medicine products, their sourcing and testing, available research, and whether regenerative treatment may be appropriate for your individual goals.

Schedule a consultation with The Re/ Clinic to learn more about your regenerative medicine options.

Call: 385-240-1000
Location: 9035 S 700 E, Sandy, UT 84070

References

1. Kuroda Y, Kitada M, Wakao S, et al. Unique multipotent cells in adult human mesenchymal cell populations. Proceedings of the National Academy of Sciences. 2010.
2. Kuroda Y, Wakao S, Kitada M, et al. Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells. Nature Protocols. 2013.
3. Wakao S, Kushida Y, Dezawa M. Research describing the biological characteristics, stress tolerance, differentiation, and reparative potential of Muse cells.
4. Kushida Y, et al. Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord. Cellular and Molecular Life Sciences. 2024. Research specifically characterizing SSEA-3-positive Muse-like cells isolated from human umbilical cord.
5. Niizuma K, et al. Randomized placebo-controlled trial of CL2020, an allogenic Muse cell-based product, in subacute ischemic stroke. Journal of Cerebral Blood Flow & Metabolism. 2023.
6. Clinical study of intravenous allogeneic Muse cells in traumatic cervical spinal cord injury. 2024. Multicenter safety and feasibility investigation of the Muse cell product CL2020.
7. Sato Y, et al. Safety and tolerability of a Muse cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia: the SHIELD trial. Stem Cells Translational Medicine. 2024.
8. U.S. Food and Drug Administration. Important Patient and Consumer Information About Regenerative Medicine Therapies. Current federal guidance regarding unapproved regenerative medicine products.
9. Utah Code § 58-1-512. Stem Cell Disclosure. Utah disclosure requirements applicable to certain non-FDA-approved stem cell therapies and advertising.