The past 2 decades have positioned stem cells at the intersection of scientific promise and clinical reality. As the body’s built-in system for repair and regeneration, stem cells have enabled breakthroughs spanning organ transplantation, drug discovery, and personalized medicine — offering an almost unlimited biological resource for therapeutic application. For all the progress made, however, biological relevance and safety challenges continue to stand between today’s research and tomorrow’s patient.
Additionally to MSC and iPSC, embryonic or pluripotent stem cells form the 3 main stem cell types. © Green Elephant Biotech.
“Stem cells” is an umbrella term for cells that share two defining capacities: the ability to self-renew almost indefinitely, and the ability to give rise to more specialized cell types. Their relevance to research, drug development, and clinical medicine is difficult to overstate, though different stem cell lineages carry distinct origins, properties, and therapeutic implications (1).
A key distinction exists between mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs) — a category that includes both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). As multipotent adult cells, MSCs are limited to differentiating into cell types of mesodermal origin, such as osteoblasts and adipocytes. PSCs, by contrast, can develop into virtually any cell type in the body, with the exception of extraembryonic structures (1).
Between 2025 and 2030, the global stem cell market is projected to grow at a compound annual growth rate of 11.41%, driven primarily by continued advances in regenerative medicine and tissue engineering (2). A landmark moment came back in 2024, when Ryoncil became the first MSC-based therapy to receive approval from the Food and Drug Administration (FDA), representing a development that continues to fuel the growing number of stem cell clinical trials to this day (3).
Having previously explored the precision medicine concept and the distinction between autologous and allogeneic therapeutic approaches, this entry turns to the promises and technical challenges of patient-centric stem cell therapies. Whether you approach this topic as a scientist or from a different professional background, the biological and past ethical considerations surrounding MSCs and iPSCs outlined below are likely to resonate with you.
Stem cells are not all the same and neither are each lineage’s applications
To date, MSCs have accumulated a greater number of established treatments than iPSCs, having been the subject of more clinical trials and representing the more clinically mature cell type (4). Despite this, broadly accepted standards for MSC characterization and criteria for therapeutic success remain surprisingly absent. Only 18% of published studies refer to the criteria established by the International Society for Cell & Gene Therapy (ISCT), fragmenting the available evidence base and complicating the interpretation of research findings (1).
The debate surrounding PSCs is no less complex. Prior to the identification of the Yamanaka factors, namely – Oct4, Klf4, Sox2, and c-Myc, in 2006, efforts to induce cellular differentiation were met with considerable resistance, largely due to the ethical concerns associated with sourcing these cells. The development of iPSC reprogramming techniques redirected attention towards the heterogeneity challenges inherent to the process, as well as the risks of high tumorigenicity and incomplete cellular maturation (1, 5).
Both MSC and iPSC approaches were nonetheless put to the test during the COVID-19 pandemic, in both therapeutic and preventative contexts. In the case of MSCs, stem cell transplantation was reported to significantly improve lung function in patients with 2019-nCoV pneumonia within two days. Infusion of MSC-derived exosomes demonstrated anti-inflammatory properties and promoted tissue regeneration under similar conditions. Given that MSCs can be sourced from a range of tissues, including bone marrow, dental pulp, and skin, their associated therapies are considered minimally invasive for the patient (4).
In COVID-19-related disease, iPSCs were widely applied to the generation of organoids as pathophysiological models. As the infection is known to affect organs beyond the lungs, such as the heart, brain, and liver, the value of modelling disease in organoids derived from a patient’s own somatic cells lies in their preventative potential. In one example, the use of a kidney organoid enabled the identification of molecular pathways showing elevated activity in COVID-19 patients linked to fibrosis formation, subsequently informing the development of targeted treatments for this subgroup (4).
Reprogramming protocols of iPSCs — a curse in disguise for the biophamaceutical industry
One of the most significant considerations in iPSC generation concerns the method used to reprogram somatic cells — a process that has conventionally relied on retroviral and lentiviral vectors. The random integration of viral material into the host genome, combined with ectopic transcription of the Yamanaka factors, represents two impactful mechanisms underlying tumorigenesis and the initiation of malignant neoplasms. Genomic instability, a well-established hallmark of cancer, can be further amplified by pre-existing mutations in the donor cell or accumulated as a consequence of long-term expansion (1).
A second concern relates to epigenetic memory or the retention of residual epigenetic signatures, inclusive of methylation patterns and histone modifications, from an iPSC’s somatic cell of origin, influencing its subsequent differentiation capacity. Evidence suggests that just as a somatic cell’s origin dictates its distinct DNA methylation profile — whether derived from umbilical cord cells or neonatal keratinocytes — extensive passaging during reprogramming cannot fully erase that cellular identity. While this may appear less immediately serious than cancer risk, this bottleneck carries substantial implications for the industrial-scale production of iPSC-derived cell types (5).
The iPSC reprogramming process itself has been reported to achieve success rates of only 0.01% to 0.1%, underscoring how labor-intensive and time-consuming it remains at commercial scale (7). The challenges associated with downstream differentiation protocols, such as those required to produce dopaminergic neurons or pancreatic beta cells, are well recognized by established market players including BlueRock Therapeutics and Vertex Pharmaceuticals, who cite consistent purity and reduced batch-to-batch variability as ongoing priorities (6).
While MSCs are not entirely free from heterogeneity, their large-scale manufacturing for clinical use has a longer and more established history. Fixed-bed bioreactors, for instance, have been developed specifically for this human cell line, reducing key sources of variability within GMP environments. For iPSCs, genome editing has been proposed as a means of controlling variability, though the technique carries the risk of introducing undesired off-target mutations. As the following section explores the future outlook for these consideration, it is worth noting that limited long-term safety data and constrained expansion rates for MSCs, alongside several underinvestigated aspects of iPSC biology, leave important questions unanswered (4).
Today’s drawbacks in stem cell therapy production should not overshadow the future prospects
While eliminating the risks associated with iPSC-derived therapies through a single protocol adjustment is unlikely, a number of strategies and ongoing developments hold genuine promise for improving the situation. Fluorescence-activated cell sorting (FACS) and magnetic bead-based sorting (MACS), for example, can be used to screen iPSC colonies and selectively remove residual or undifferentiated stem cells. When applied to iPSC-derived neural progenitor cells, both methods increased the proportion of healthy stem cells from a range of 69-87% to 80-99% (8).
Certain contamination risks may nonetheless persist following such screening, which is why some researchers have instead directed their efforts towards improving the reprogramming protocols themselves, with the aim of shielding patients from accompanying mutations, altered telomere homeostasis, chromosomal abnormalities, and related pathologies. Some approaches involve relatively targeted adjustments: the addition of compounds like resveratrol, the incorporation of reprogramming enhancer genes (e.g., BCL-xL in patient-derived blood cells), or the use of hypoxic conditions at 5% O₂, though the effects of these modifications can be context-dependent and not always reproducible (9).
Others have turned to non-integrating reprogramming methods that eliminate the need for lenti- or retroviral vectors entirely. One such alternative, SeV — an RNA virus-based technique first applied in 2009 — was reported to achieve a success rate of 92% in a replication study using reprogrammed fibroblasts. Here, success was defined according to long-term stability, viability, sterility, and iPSC quality, pointing towards a more reliable pathway for the generation of high-quality stem cells at scale (6).
Understanding these developments carries equal importance for patients, as iPSCs hold considerable promise for reducing the costs of clinical trials, enabling decentralized therapy manufacturing, and ultimately supporting faster and more affordable access to regenerative treatments. Among drug development applications facilitated by iPSCs is toxicity profiling, where cytotoxicity assays allow for the screening of 5,000 to 10,000 compounds at the pre-clinical stage. The same principle applies to animal model replacement, where the use of biologically relevant iPSC-based systems can reduce both financial expenditure and the ethical burden associated with animal research (4).
The journey of stem cell therapy from early-stage research to regulated clinical use reflects both the ambition and the complexity of patient-centric medicine. From MSC transplantation improving outcomes in COVID-19 patients to iPSC-derived organoids uncovering under-investigated molecular mechanisms, the milestones of the past two decades are worth the strive for a more productive and safer applications of the stem cells.
The path ahead demands equal honesty about what remains unresolved. Inconsistent characterization standards, reprogramming inefficiencies, and tumorigenicity risks still remain the defining obstacles. For stem cell therapy to fully deliver on its decades-long promise, the field must hold both truths simultaneously — advancing what works while addressing what does not, always with the patient as the central measure of success.
This approach is not an unfamiliar one to the Green Elephant Biotech, where we build to increase a workflow’s productivity and make therapy development more affordable. Our dynamic adherent bioreactor, Archimedes® One, encompasses full process control with automated harvesting, without taking away simplicity or familiarity. Interested to learn more?
Find the latest product one-pager, along with information on the Early Access Program and its benefits, on the official Archimedes® One page.
References:
- Panferov, E, Dodina, M, Reshetnikov, V, Ryapolova, A, Ivanov, R, Karabelsky, A, Minskaia, E, Induced Pluripotent (iPSC) and Mesenchymal (MSC) Stem Cells for In Vitro Disease Modeling and Regenerative Medicine (2025), Int J Mol Sci 26: 5617-72. doi: 10.3390/ijms26125617.
- Stem Cells Market (2025-2030). (2024). Grand View Research. Available https://www.grandviewresearch.com/industry-analysis/stem-cells-market (Accessed 28 April 2026).
- Stem cell therapy benefits — repair, replace, restore. (2025). Katharina Günther, Green Elephant Biotech. Available https://greenelephantbiotech.com/blog/stem-cell-therapy-benefits-repair-replace-restore/ (Accessed 28 April 2026).
- Thanaskody, K, Jusop, AS, Tye, GJ, Kamarul Zaman, WSW, Dass, SA, Nordin, F, MSCs vs. iPSCs: Potential in therapeutic application (2022), Front Cell Dev Biol 10: 1005926-57. doi: 10.3389/fcell.2022.1005926.
- Limitations of Induced Pluripotent Stem Cells in 2026. (2026). BioInformant Team. Available https://bioinformant.com/limitations-of-ipscs (Accessed 29 April 2026).
- Pozner, T, Grandizio, C, Mitchell, MW, Turan, N, Scheinfeldt, L, Human iPSC Reprogramming Success: The Impact of Approaches and Source Materials (2025), Stem Cells Int 1: 2223645-53. doi: 10.1155/sci/2223645.
- Singh, A, Jasra, I, Mouhammed, O, Dadheech, N, Ray, N, Shapiro, J, Towards Early Prediction of Human iPSC Reprogramming Success (2023), MELBA 14: 390-407. doi: 10.59275/j.melba.2023-3d9d.
- Bowles, KR, W, JTC, Qian, L, Jadow, BM, Goate, AM, Reduced variability of neural progenitor cells and improved purity of neuronal cultures using magnetic activated cell sorting (2019), PLoS One 14: e0213374-92. doi: 10.1371/journal.pone.0213374.
- Hayashi, Y, Human Mutations Affecting Reprogramming into Induced Pluripotent Stem Cells (2017), AIMS Cell Tissue Eng 1: 31-46. doi: 10.3934/celltissue.2017.1.31.
