iPSC and MSCs: Transforming Regenerative Medicine

Stem cells like iPSCs and MSCs are at the forefront of curing

diseases once considered untreatable

Human induced pluripotent stem cells (iPSCs)

Stem cells have sparked a revolution in biomedical research and regenerative medicine due to their remarkable ability to self-renew and differentiate into specialized cell types. Their groundbreaking potential for life-changing applications in cell therapy and tissue engineering has opened new ways for treating previously incurable diseases. Pluripotent stem cells (1) such as embryonic (ESCs) or induced pluripotent stem cells (iPSCs or iPS cells) have the unique capability to give rise to cells from all three germ layers. In contrast, adult or tissue-specific stem cells including mesenchymal (MSCs) or neural stem cells (NSCs) are restricted to differentiating within a specific lineage. Both iPSCs and MSCs are extensively studied for their potential in disease modeling, drug development, and cell-based therapies. Successfully cultivating, expanding, and scaling up these cells (2) for cell manufacturing approaches requires precise control over the microenvironment, growth factors, and passaging techniques to maintain their stemness and differentiation potential.

Understanding iPSCs and MSCs

iPSC are generated by reprogramming somatic cells, such as patient-derived fibroblasts or blood cells, into a pluripotent state using a cocktail of transcription factors like Oct4, Sox2, Klf4, and c-Myc (OSKM factors). Reprogramming can be achieved using non-integrating methods such as mRNA transfection or Sendai virus delivery which help to ensure the clinical safety of iPS cell lines by avoiding genetic alterations (3). After reprogramming, a comprehensive characterization process is necessary using molecular and cellular assays to confirm the pluripotent state and rule out any tumorigenic potential. Morphologically, undifferentiated iPSCs typically appear as densely packed colonies of small, round cells and closely resemble ESCs. One of the most exciting features of iPSCs is their ability to differentiate into specific cell types in a virtually unlimited manner. Advanced differentiation protocols enable the efficient generation of specialized cell types such as beating cardiomyocytes, functional neurons, and liver cells, offering broad potential for personalized medicine, drug screening, and tissue engineering (4, 5). MSCs are multipotent stem cells capable of differentiating into mesodermal cells, including osteoblasts (bone cells), chondrocytes (cartilage cells), and adipocytes (fat cells). These cells are commonly isolated from a variety of sources such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs have attracted strong interest in regenerative medicine thanks to their immunomodulatory properties, allowing them to reduce inflammation and regulate immune responses. This makes them particularly valuable in the treatment of autoimmune and inflammatory diseases. Beyond their ability to modulate the immune system, they can secrete bioactive molecules supporting wound healing and angiogenesis and potentially contributing to the repair of muscular or cardiovascular tissue (6).

iPSC and MSC-Based Therapies

iPSCs and MSCs have been essential in advancing regenerative medicine, leading to significant clinical applications. In 2014, Japan became the first country to conduct a clinical trial using iPSC-derived cells, marking a historic milestone. The team successfully generated autologous retinal pigment epithelial (RPE) cells from iPSCs to treat age-related macular degeneration (AMD) by transplanting them into a patient to replace the damaged RPE cells (7). A decade later, a growing number of clinical trials worldwide explore the efficacy and safety of iPSC-derived therapies for the treatment of a wide range of diseases (8, 9). Similarly, MSC-based therapies have gained significant traction in clinical research (10,11). In December 2024, the U.S. Food and Drug Administration (FDA) approved the first MSC therapy indicated for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in pediatric patients (12). This landmark approval underlines the immense therapeutic potential of MSCs in treating severe inflammatory conditions. These achievements in iPSC and MSC-based therapies emphasize the transformative role of adherent stem cells in developing novel treatments for diseases once considered untreatable. Culturing iPSCs and MSCs for clinical use requires precise control of growth conditions, passaging techniques, and quality assurance to maintain their regenerative properties. While iPS cells provide an unlimited supply of patient-specific cells, MSCs remain a key tool in regenerative therapies due to their immunomodulatory and tissue-repair capabilities.

The advancement of stem cell research, particularly involving iPSCs and MSCs, has paved the way for innovative therapeutic strategies. As the field progresses, the ability to efficiently culture and expand these stem cell types will be critical for their translation into widespread clinical use. Traditional two-dimensional culture systems, such as T-flasks and multi-layered flasks, often fall short of meeting the demands for large-scale cell production due to limitations in surface area and scalability. Did you know that the CellScrew® system by Green Elephant Biotech has been designed to overcome these bottlenecks sustainably? Available in various sizes and 3D-printed from PLA, the CellScrew® allows for seamless scaling of adherent cell cultures, tailored to both research and industrial-scale production needs. By enabling the production of clinically relevant cell quantities, Green Elephant addresses the demand for stem cell-based therapies and helps to translate basic research into viable clinical treatments.

References

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6. Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 8, 726–736 (2008). https://doi.org/10.1038/nri2395

7. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M. Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017 Mar 16;376(11):1038-1046. doi: 10.1056/NEJMoa1608368. PMID: 28296613.

8. Hui KK, Yamanaka S. iPS cell therapy 2.0: Preparing for next-generation regenerative medicine. Bioessays. 2024 Dec;46(12):e2400072. doi: 10.1002/bies.202400072. Epub 2024 Jun 25. PMID: 38922935.

9. Madrid M, Sumen C, Aivio S, Saklayen N. Autologous Induced Pluripotent Stem Cell-Based Cell Therapies: Promise, Progress, and Challenges. Curr Protoc. 2021 Mar;1(3):e88. doi: 10.1002/cpz1.88. PMID: 33725407.

10. Bieback K, Schallmoser K, Klüter H, Strunk D. Clinical Protocols for the Isolation and Expansion of Mesenchymal Stromal Cells. Transfus Med Hemother. 2008;35(4):286-294. doi: 10.1159/000141567. Epub 2008 Jul 17. PMID: 21512644; PMCID: PMC3076361.

11. Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell. 2021 Oct 7;28(10):1708-1725. doi: 10.1016/j.stem.2021.09.006. PMID: 34624232.

12. FDA, FDA Approves First Mesenchymal Stromal Cell Therapy to Treat Steroid-refractory Acute Graft-versus-host Disease, 2024 Dec 18, Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-mesenchymal-stromal-cell-therapy-treat-steroid-refractory-acute-graft-versus-host