Solving The Stem Cell Consistency Conundrum With iMSCs
By Robert H. Pierce, MD, chief scientific officer, Ernexa Therapeutics
For years, mesenchymal stem cells (MSCs) have captured the imagination of scientists and clinicians for their therapeutic versatility – their ability to dampen inflammation, promote tissue repair, and influence immune responses in ways that traditional biologics could not easily replicate. Yet, despite their promise, anyone who has worked closely with MSCs knows their biggest limitation: inconsistency.
Donor-to-donor variability, finite expansion potential, and sensitivity to culture conditions have long hampered the reproducibility and scalability of MSC-based products. These constraints have kept the field hovering at the edge of large-scale clinical translation, without fully breaking through.
Now, a new generation of MSC-like cells – induced mesenchymal stem cells, or iMSCs, is emerging from the intersection of stem cell biology and manufacturing science. Derived from induced pluripotent stem cells (iPSCs), iMSCs offer a tantalizing solution to the consistency problem that has limited traditional MSCs for decades. If we can guide this technology with precision – scientifically, technically, and regulatorily – iMSCs could redefine the very foundation of cell therapy manufacturing.
How iMSCs Differ – And Why It Matters
Conventional MSCs are isolated directly from tissues such as bone marrow, adipose, or umbilical cord. No matter how careful the process, biological diversity from donor sources inevitably introduces variability in growth characteristics, potency, and even therapeutic activity.
iMSCs, by contrast, are derived from iPSCs, which means they originate from a single clonally defined cell line that can self-renew indefinitely. This makes it possible to create a stable master bank of iPSCs and then reproducibly differentiate them into iMSCs, generating a nearly limitless, uniform supply.
In other words, what once required multiple donors and complex logistics can now be manufactured with precision and scale. This distinction has profound implications for reproducibility, quality control, and ultimately, regulatory confidence.
Functionally, iMSCs retain many of the hallmarks of primary MSCs, including secretion of cytokines and growth factors that influence inflammation and repair. But they also exhibit unique transcriptional and epigenetic profiles. Some of these differences may even enhance their therapeutic potential, though we are only beginning to understand how.
Manufacturing For Consistency, Scale, And Quality
While this is just the beginning for the power of iMSCs, if there is one area where iMSCs already stand apart, it’s manufacturing. Because all product batches can trace back to the same iPSC line, the degree of consistency achievable is unprecedented in the MSC space. This single-source origin makes allogeneic, off-the-shelf production feasible in ways that are simply not practical for donor-derived MSCs.
But reproducibility does not happen by default. It requires careful orchestration. Differentiation must be efficient and robust, with each step validated for purity and yield. Upstream processes should integrate closed-system bioreactors and defined media, while downstream steps like harvest, wash, and formulation must be engineered to preserve viability and potency.
Cryopreservation and cold chain management are particularly critical. MSCs, and by extension iMSCs, are notoriously sensitive to freeze-thaw stress. Even slight changes in cooling rate or cryoprotectant composition can alter cell function post-thaw. Developing reliable automated systems for cryopreservation – ideally with real-time monitoring and quality checkpoints – will be essential to enabling global distribution.
For early-stage companies, outsourcing parts of this workflow can make sense. Partnering with CDMOs that have iPSC expertise can shorten development timelines and ensure regulatory-grade GMP production. The balance between internal control and external support will vary by organization, but getting it right can make or break a program’s path to IND.
Engineering Flexibility: Expanding The Design Space
One of the most compelling advantages of iMSC technology is its openness to genetic modification. Because genetic edits can be introduced at the iPSC stage – before differentiation – developers can precisely engineer the resulting iMSCs to have enhanced or customized properties.
That could mean correcting disease-associated mutations, adding resistance to oxidative stress, optimizing migration patterns, or even programming iMSCs to secrete therapeutic proteins on demand. Conventional MSCs simply do not offer this flexibility, as their limited proliferative capacity and resistance to transfection make meaningful engineering difficult.
Of course, every genetic modification introduces added complexity and regulatory scrutiny. Developers must demonstrate genomic stability, absence of off-target edits, and functional predictability, but with modern genome editing tools and robust analytical pipelines, these are manageable challenges.
Leveraging Intrinsic Homing Ability: Building The Perfect Trojan Horse
MSCs exhibit an intrinsic ability to home to and infiltrate into inflamed tissues, which reflects their normal function in aiding tissue repair and regeneration. Similar inflammatory signals lead to MSC recruitment and engraftment into tumor tissue, reflecting the similarity between the inflamed tissue associated with wounds and tumors – tumors have been dubbed “wounds that don’t heal.” By taking advantage of tissue-homing, developers can deliver synthetic iMSCs engineered to express immunomodulatory or other therapeutic factors selectively to target tissues, which helps reduce off-target exposure and potential toxicity.
Tackling Tumorigenicity: Designing Safety From The Ground Up
Because iMSCs originate from PSCs, tumorigenicity is an understandable concern. The key question is whether any residual iPSCs remain in the final product. The good news is that differentiation and purification protocols have become increasingly effective at driving cells firmly out of pluripotency, and sensitive assays now allow detection of even trace pluripotent markers.
Safety strategies do not stop there. “Suicide switch” systems – engineered genetic constructs that can be activated if unwanted proliferation occurs – are being explored as an additional safeguard. Combined with thorough release testing, these approaches are building confidence that iMSCs can be manufactured safely and consistently.
Regulatory Pathways: Navigating A New Frontier
Regulators are well versed in reviewing both MSC-based therapies and iPSC-derived products, but iMSCs sit at the intersection of those two worlds, representing a new category with few established precedents to follow. That novelty makes proactive engagement with agencies especially important. Programs like the FDA’s INTERACT meetings and EMA’s Innovation Task Force provide valuable venues to shape expectations early – particularly around master cell bank characterization, residual iPSC testing, and potency assay development.
In the absence of a defined regulatory framework, the onus falls on innovators in this space to help set the benchmarks, demonstrating what rigorous comparability, consistency, and safety look like for this emerging product class. As preclinical and clinical evidence accumulates, regulators will gain the confidence and data foundation needed to formalize guidance. Until then, transparency, thorough documentation, and early collaboration remain the most effective ways to build trust and move the field forward.
Looking Ahead: Steering The Field Wisely
The advancement of iMSs is moving quickly, and now, thoughtful direction is critical. We have seen promising technologies falter when enthusiasm outpaced scientific grounding or manufacturing discipline. iMSCs offer tremendous potential, and now, collaboration between researchers, regulators, and manufacturers is beginning to set clear standards and uphold rigorous quality systems.
If we steer this technology with care, iMSCs could transform how we think about cell therapies. They could provide the reliability and scalability of a biologic drug, with the adaptability and intelligence of living cells. That is not just incremental progress. It is a new paradigm for how cellular medicines are made and delivered.
About The Author:
Robert H. Pierce, MD, is the chief scientific officer of Ernexa Therapeutics, which is developing innovative cell therapies for the treatment of advanced cancer and autoimmune disease. Its lead cell therapy product, ERNA-101, is being developed for the treatment of ovarian cancer. Dr. Pierce is an anatomic pathologist who brings more than two decades of scientific leadership and experience managing large teams dedicated to drug development in both academia and industry, with particular emphasis on immunology and oncology.