Part 1
Why this unusual population of adult stem cells is attracting attention in regenerative medicine
This is the first in a series of articles about stem cells.
When most people hear the words stem cell, they tend to think of stem cells as one category. They are not. Different stem cell populations can vary dramatically in where they come from, how well they survive, where they travel after entering the body, what signals they release, and what they may ultimately become.
In regenerative medicine, those differences may matter as much as the number of cells being administered.
One of the most intriguing populations being studied today is the MUSE cell, short for Multilineage-differentiating Stress-Enduring cell. Professor Mari Dezawa and colleagues first characterized MUSE cells as a naturally occurring population within adult mesenchymal tissues. They can be identified in part by expression of SSEA-3, a surface marker associated with pluripotency.
Unlike induced pluripotent stem cells, MUSE cells do not require genetic reprogramming to acquire their unusual biology.
What makes MUSE cells especially interesting is not one single feature. It is the combination of properties contained within the same cell.
1. Pluripotent-Like Differentiation
Most adult mesenchymal stem or stromal cells have a relatively restricted range of differentiation. MUSE cells appear to have broader developmental potential.
Experimental studies have shown that they can generate cells displaying characteristics of all three embryologic germ layers, ectoderm, mesoderm, and endoderm, and they express pluripotency-associated genes including Oct3/4, Sox2, and Nanog.
I prefer the term pluripotent-like because MUSE cells should not simply be equated with embryonic stem cells or induced pluripotent stem cells. They share some important features of pluripotency, but their biological behavior differs distinctly.
2. Built to Survive Stress
The name itself tells us something important: the “SE” in MUSE stands for Stress-Enduring.
That may be highly relevant in regenerative medicine because injured tissue is often a hostile environment. It can be low in oxygen, inflammatory, oxidatively stressed, metabolically altered, and structurally disrupted.
MUSE cells were originally identified in part because a small population survived severe cellular stress that many surrounding cells did not tolerate.
That leads to a simple but important point: it is not enough to put a regenerative cell into the body. The cell must also survive the environment it encounters.
3. A Biological GPS System
When tissue is injured, damaged cells release biochemical distress signals. One of them is sphingosine-1-phosphate, or S1P.
MUSE cells express a receptor called S1PR2 that allows them to respond to this signal. In experimental models, the S1P-S1PR2 pathway helps guide circulating MUSE cells toward areas of tissue injury. Blocking the pathway markedly reduces that preferential migration.
The injured tissue sends a distress signal. The MUSE cell has a receptor that helps it respond.
This differs from simply placing cells into the circulation and hoping enough eventually reach the target.
Much of the detailed mechanistic evidence still comes from laboratory and animal work, but the pathway provides a compelling biological explanation for injury-directed homing.
4. An Unusual Immune Profile
MUSE cells also appear to interact with the immune system in an unusual way.
Donor-derived cells would normally trigger some degree of immune recognition, yet MUSE cells show an immune-tolerant, immunomodulatory profile. HLA-G, a molecule associated with immune tolerance, appears to be part of that biology, along with other regulatory mechanisms.
This is more accurate than saying that MUSE cells simply “have no HLA.” They do interact with the immune system. What appears different is how that interaction is regulated.
That immune profile is one reason allogeneic MUSE-cell products have moved into clinical research. In a randomized study of subacute ischemic stroke, an allogeneic MUSE-cell product was administered without immunosuppressive treatment.
Whether that experience generalizes across different products and diseases remains under investigation.
5. The Secretome: Cells as Biological Communicators
One major shift in regenerative medicine has been the realization that cells do not have to physically replace damaged tissue to influence healing.
Cells also communicate.
They release cytokines, growth factors, proteins, and extracellular vesicles that can influence surrounding cells. Collectively, these signals are known as the secretome.
MUSE cells appear to produce a biologically active secretome associated with immune regulation, cell survival, extracellular matrix remodeling, and repair.
That means they may influence damaged tissue in two ways: through direct participation in tissue repair and through paracrine signaling that changes the local biological environment.
Regeneration is not just cell replacement. It is communication within an ecosystem.
6. Pluripotent-Like Without the Same Teratoma Behavior
Classical pluripotent cells, such as embryonic stem cells and induced pluripotent stem cells, have enormous developmental potential. However, uncontrolled pluripotent cells can form teratomas.
MUSE cells appear to behave differently.
Although they express pluripotency-associated markers and differentiate across the three germ layers, they show lower proliferative activity and have not formed teratomas in commonly cited preclinical models.
That does not make any cell therapy risk-free. Long-term safety must ultimately be established in rigorous human studies.
But the combination of broad differentiation potential and a different preclinical tumor profile is one reason MUSE cells are scientifically unusual.
Why the Combination Matters
Any one of these characteristics would be interesting. Together, they create a more compelling biological profile: a cell that may survive a hostile environment, recognize injury signals, migrate toward damaged tissue, communicate through its secretome, and retain broader differentiation potential without the same preclinical teratoma behavior seen with classical pluripotent stem cells.
That is why MUSE cells should not simply be viewed as another version of a conventional MSC preparation.
It also highlights a point that is easy to miss in regenerative medicine: cell identity may be just as important as cell quantity.
Two vials containing similar numbers of cells may behave very differently if the biology of those cells is different.
From Infusion to Potential Repair
Together, these properties suggest a different model of cell therapy.
MUSE cells enter the circulation. Injured tissue releases signals such as S1P. The cells detect those signals through receptors including S1PR2, and they may migrate preferentially toward the injury.
Once there, they may influence the local environment through secretome signaling and, under appropriate conditions, potentially participate more directly in tissue repair.
Biology in a patient is more complex than any diagram.
Not every infused cell will reach an injury site, not every injury produces the same signals, and findings from animal experiments cannot be assumed to translate to the same degree in humans.
But this framework helps explain why MUSE cells have attracted such interest.
Where the Science Stands
MUSE cells are no longer confined entirely to laboratory experiments.
Human research has included a three-patient first-in-human study after acute myocardial infarction and a 35-patient randomized, double-blind, placebo-controlled trial in subacute ischemic stroke.
These studies are encouraging, but they remain small and disease-specific.
Results in one condition cannot simply be extrapolated to another, and larger controlled trials are still needed to establish efficacy and long-term safety.
In the United States, MUSE-cell therapy remains investigational and is not an FDA-approved treatment for these conditions.
At PUR-FORM, I believe we can be excited by emerging biology while remaining equally clear about what has and has not yet been demonstrated.
A Different Question for Regenerative Medicine
For years, one of the most common questions in cell therapy has been:
How many stem cells are we giving?
That remains important.
But a more meaningful question may be:
What can those cells actually do once they enter the body?
- Can they recognize injury?
- Can they reach it?
- Can they survive when they arrive?
- Can they communicate with the surrounding tissue?
- Can they influence inflammation and the extracellular environment?
- Can they participate in meaningful repair, and can they do it with an acceptable safety profile?
Those questions move regenerative medicine beyond simple cell counts and toward something more important: cell biology.
MUSE cells are intriguing because their biology addresses several of those questions at once.
Dr. P
