The remarkable propensity of mesenchymal stem cells (MSCs) for self-renewal, multi-lineage differentiation and immune-modulatory activity has attracted much attention within the cell therapy area, from their potential in cell therapies and research models to their emerging role in the fight against cancer.
MSC Properties Are Greatly Influenced by Source
Despite their great potential, MSC-based therapies have not yet made it to the clinic, and a number of challenges must be addressed before their full therapeutic potential can be realized. One major challenge is their lack of uniformity, such that MSCs vary depending on their external and tissue environment, their original tissue source, and the isolation method used.
Not only does lack of uniformity impede the standardization of MSC isolation and cultivation protocols, but it also complicates the task of ensuring that in vivo MSC activity will perpetuate the same desired function as predicted ex vivo. This is because MSC functionality is largely dependent upon on the secretion of soluble factors such as growth factors and cytokines, which is influenced greatly by the surface structure of the MSC microenvironment as well as the organ of MSC origin; for example, kidney-derived MSCs specifically produce and secrete hepatocyte growth factor. It is not yet known whether or not it is possible to preserve such organotypic features during MSC cultivation for therapeutic purposes.
As summarized in one of our earlier posts, a set of unified and minimal criteria to define MSCs was established by the International Society for Cellular Therapy (ISCT) in 2006 (1), and this has since become a widely accepted practice in the field. While this has helped to streamline research efforts into MSCs, a greater understanding of the distinct properties and capabilities of MSCs depending on their source would benefit researchers in designing consistent protocols for the development of tailored MSC-based therapeutics for a range of target diseases. In this post, we provide a brief overview of the MSCs that originate from three of the commonly used MSC sources today, namely bone marrow, adipocytes and induced pluripotent stem cells (iPSCs).
Bone Marrow-Derived MSCs
Bone marrow has traditionally been the major source of human MSCs. However, despite being a rich source of hematopoietic stem cells, the frequency of MSCs in the bone marrow is very low at 0.001–0.01%, and these numbers decline with age (2). In addition, the collection of bone marrow-derived MSCs (BM-MSCs) from patients is an invasive and painful procedure that requires general anesthesia, thus limiting their supply for therapeutic applications and arousing interest in alternative sources of human MSCs. Nonetheless, BM-MSCs continue to attract interest for their potential in immunomodulation and the treatment of graft versus host disease (GvHD) after organ transplantation.
Adipose Tissue-Derived MSCs
Studies on the excess adipose tissue obtained from fat-reducing surgeries has revealed adipose tissue to be a very rich source of MSCs, and this has sparked intense interest in harnessing adipose tissue-derived MSCs (AdMSCs) for therapeutic purposes. Since they can be isolated via minimally invasive procedures, AdMSCs have become important candidates for autologous and allogeneic stem cell-based therapies and tissue engineering. Morphologically and phenotypically, AdMSCs are similar to BM-MSCs, but they are significantly easier to harvest, and a typical isolation yields much greater numbers than bone marrow isolation.
BM-MSCs vs. AdMSCS
Given their abundance and ease of access, AdMSCs might seem like the obvious choice for clinical applications over BM-MSCs, but how do these cells compare otherwise?
As mentioned earlier, BM-MSCs and AdMSCs are morphologically similar, with comparable cell surface expression markers. However, the similarities stop here, as studies have found considerable biological differences between their capacities for differentiation and proliferation (3, and references therein). Generally, AdMSCs show a stronger proliferative potential than BM-MSCs, and cytokine and chemokine expression profiles are quite distinct between the two sources. For example, AdMSCs are associated with higher secretion levels of proangiogenic growth factor e.g., vascular endothelial growth factor (VEGF) than BM-MSCs, suggesting that AdMSCs may be suitable for therapeutic applications requiring angiogenesis, such as the treatment of ischemia and tissue engineering. On the other hand, BM-MSCs preferentially differentiate into bone and cartilage, whereas AdMSCs preferentially differentiate into adipocytes. This may be the result of a set of signature genes that is differentially regulated between the two cells types during maturation, in addition to the influence of their tissue-specific microenvironments.
In the end, which MSC source is better for therapeutics is a complex question that can only be answered by tried and tested efforts to move MSC-based therapies into the clinic, and the efforts to date have been the subject of a recent comprehensive review (5).
What About iPSC-derived MSCs?
The attraction of using induced pluripotent stem cell-derived MSCs (iPSC-derived MSCs) lies in the possibility to establish a consistent and inexhaustible source of human MSCs that is amenable to up-scaling, while avoiding limited extraction potentials, batch-to-batch variations, and dealing with MSCs from diverse sources such as bone marrow or adipose tissue. In addition, the use of iPSC-derived MSCs completely circumvents the need to isolate MSCs either from healthy individuals or patients. In theory, iPSC-derived MSCs can be programmed/manipulated/stimulated to differentiate into any cell lineage.
Most iPSCs are generated using the so-called Yamanaka factors; Oct3/4, Sox2, Klf4, and c-Myc, the overexpression of which can induce pluripotency in both mouse and human somatic cells (5). However, c-myc is an oncogene and iPSCs generated with Yamanaka factors are thus associated with teratoma formation in transplanted animals, which is obviously a highly undesirable situation in a therapeutic setting and precludes the use of Yamanaka factors in the manufacture of iPSC-based therapies. This has prompted the development of alternative methods to generate iPSCs, such as Tempo Bioscience’s in-house proprietary method, which is feeder-free, serum-free, viral/genetic-elements-free, and integration-free method for reprogramming somatic cells to iPSCs.
Owing to the possibility to establish consistent and large-scale cultures as described above, iPSC-derived MSCs are also widely used in research settings. For example, Tempo’s iMSC™ are human iPS-derived MSCs that are well suited for developmental and lineage differentiation studies, to discover and characterize new biomarkers, and to perform large-scale compound screening. Uniquely, Tempo’s iMSCs grow as a monolayer as opposed to in suspension, increasing the feasibility and practically of screening and other experiments.
While a number of pre-clinical success stories exist for iPSC-derived MSCs, insufficient progress has been made in the clinical implementation of iPSC-derived therapies so far. However, there is a cause for hope with one iPSC-MSC-based clinical trial underway to investigate their potential to treat steroid-resistant acute graft versus host disease, while a recent report on attempts to treat age-related macular degeneration with iPSC-derived MSCs yielded promising results (6).
Get in Touch!
To comment on this post, or to hear more about MSCs or any of Tempo’s MSC offerings, drop us an email at support@tempobioscience.com.
References:
- Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
- Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, et al. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem. 2006;97(4):744-54.
- El-Badawy A, Amer M, Abdelbaset R, Sherif SN, Abo-Elela M, Ghallab YH, et al. Adipose Stem Cells Display Higher Regenerative Capacities and More Adaptable Electro-Kinetic Properties Compared to Bone Marrow-Derived Mesenchymal Stromal Cells. Sci Rep. 2016;6:37801.
- Galipeau J, Sensébé L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell. 2018;22(6):824-33.
- Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-72.
- Souied E, Pulido J, Staurenghi G. Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017;377(8):792.
Article by Karen O’Hanlon Cohrt PhD. Contact Karen at karen@tempobioscience.com.
Karen O’Hanlon Cohrt is a Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen moved to Denmark and held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for writing helps her to keep abreast of exciting research developments as they unfold. Follow Karen on Twitter @KarenOHCohrt. Karen has been a science writer since 2014; you can find her other work on her portfolio.
