We gave you an introduction to mesenchymal cells (MSCs) in one of our earlier Cell of the Month posts. Staying with the theme of recapitulating in vivo development processes (check out our most recent post on organoids), we wanted to take a closer look at MSCs and their two applications that have attracted most attention to date – cellular therapies and research models.
A Quick Recap on MSCs
Before we get into the details, let’s take a quick recap on our ‘cell of the month’ MSCs. These are a class of multipotent stromal cells that can self-generate and differentiate into multiple mesenchymal lineages such as: chondrocytes, osteoblasts and adipocytes. They can be easily isolated from the bone marrow, adipose tissue, the umbilical cord, fetal liver, muscle, and lung, and can be successfully expanded ex vivo. MSCs display donor-specific and organ-specific biomarker expression patterns, which are important aspects for research and therapeutic development purposes.
Isn’t Cellular Therapy Old News?
Yes, the idea of injecting cells into an individual to treat or cure disease is old news. Cellular therapies began to emerge in the 1990’s as a completely novel approach to treat disease, and today huge investment is being pumped into these therapies with the belief that they hold the key to treat diseases that are intractable to treatment with conventional drugs. In simple terms, cellular therapy involves introducing living cells or tissue directly into an individual in order to treat a disease. Stem cell therapy is just one type of cellular therapy (T cell therapy is another), and efforts to develop stem cell therapies are motivated largely by the remarkable properties of these cells:
- They are unspecialized cells with the ability to renew themselves for long periods of time without undergoing significant changes in their general properties.
- They can differentiate into various specialized cell types under certain physiological or experimental conditions.
However, despite the obvious therapeutic potential of stem cells, and intense developmental efforts over the past few decades, they have not yet proven to be the miracle or cure-all treatment that they are often hailed to be. There are a number of players in the stem cell therapy field, and while MSCs are the most prominent player, it is worth taking a look at some of the others to appreciate why MSCs have gained so much traction in recent years.
So Who Are MSCs up Against?
Hematopoietic Stem Cells
Hematopoietic stem cells (HSCs) have been used in allogeneic cell therapy since the 1960s. Here, a recipient receives cells from a genetically similar donor, for example, a first degree relative. The best-known examples of HSC therapy are bone marrow transplants, which have been the key component in the treatment of blood cancers for decades.
The success of bone marrow transplantation keeps the HSC field moving, with many researchers looking at combining HSC therapy with advances in gene editing as a way to correct genetic defects in a patient’s own bone marrow stem cells. The first of these therapies got the green light in Europe last year, when GSK got approval for Strimvelis, a HSC therapy to treat patients with a very rare form of Severe Combined Immunodeficiency (SCID). The patient’s own cells are isolated and genetically modified, thus correcting the immunodeficiency and simultaneously avoiding the risk of graft versus host disease, which still affects around 1 in 3 bone marrow transplant recipients. Although we can’t understate the important of HSC therapies, they are limited to the treatment of blood disorders.
Embryonic and Induced Pluripotent Stem Cells
The successful isolation of pluripotent embryonic stem (ES) cells from the inner cell mass of early-stage embryos in the 1980s was a turning point in biological research. ES cells can give rise to all known cell lineages and are therefore considered by many be the most promising cells for regenerative medicine for any tissue type.
Obvious ethical concerns surrounding the source of ES cells have since led to the development of protocols for induced pluripotent stem (iPS) cells, which were first reprogrammed from adult somatic cells by researchers by researchers at Kyoto University, Japan in 2006 (1). iPS cells share many properties with ES cells, and are free of ethical concerns. However, many of the available reprogramming protocols rely on viral, lentiviral or other genetic integration methods, and are associated with a risk for teratoma (a multi-tissue tumor that often comprises bone, hair, and muscle) formation. This is a significant concern for cells that are reprogrammed for clinical purposes. Newer, integration-free protocols such as those used in the development of Tempo’s iPS cell products and Tempo’s iPS-derived cell products abrograte the risk for teratoma formation.
Are MSCs the Rising Star in the Stem Cell World?
Since MSCs are neither associated with teratoma formation nor ethical concerns, they have gained increased interest for use in the clinic, and it can even be argued that MSCs are now the preferred option for cell therapy.
The first clinical trial involving MSCs was described in 1999. Here, allogeneic bone-marrow derived MSCs were used to treat a small group of children with the rare skeletal condition osteogenesis imperfecta (2). The results were promising with an increase in growth, bone mineral content and a reduction in the incidence of bone fracture observed in all study participants. In the two decades that have since passed, efforts have exploded to fully exploit MSCs as an emerging class of therapeutics to regenerate damaged tissue and treat diseases such as heart disease, liver cirrhosis, brain spinal cord injury, cartilage and bone injury, Crohn’s disease, neurodegenerative disease, graft‐versus‐host disease, and others. MSCs are also under investigation as novel cell-based vehicles for cancer therapies. A current search of the NIH Clinical Trials website using ‘mesenchymal stem cells’ as keywords reveals 197 studies currently recruiting for participants worldwide.
A Lot Done, a Lot More to Do!
Like many novel therapeutic strategies, the prospect of using MSCs in the clinic was initially seen as a massive advance in medicine. They have now been used in the clinic for about 10 years, and from animal models to clinical trials, MSCs hold promise for the treatment of numerous diseases, mainly tissue injury and immune disorders. However, no MSC-based clinical trials have yet resulted in FDA-approved treatments, strongly illustrating that many challenges need to be tackled before their widespread use in the clinic.
In an attempt to streamline research efforts with MSCs, the International Society for Cellular Therapy (ISCT) established the following unified and minimal criteria to define MSCs in 2006 (3).
- Must exhibit adherence to plastic when grown in standard culture conditions.
- Must be positive for the following surface markers CD73, CD90 and CD105, but not express hematopoietic markers CD45, CD34, CD14, CD11b, CD19, CD79a or HLA-DR
- Must exhibit capacity for trilineage mesenchymal differentiation into osteoblasts, adipocytes and chondrocytes
A number of major challenges remain:
- The surface markers and gene expression profiles and morphologies exhibited by MSCs vary depending on their external and tissue environment, which complicates the task of ensuring that the in vivo activity of MSCs will have the same desired function as predicted ex vivo.
- To solve the first challenge and to better understand the therapeutic mechanisms of MSCs in vivo, we need to know more about the interactions that occur between MSCs and their surrounding inflammatory environment once transplanted.
- Gaps in our knowledge relating to the administration and monitoring of clinical efficacy also need to be filled:
- The optimal source of MSCs for each target disease is not known
- It is often not known which route of administration is optimal for a given disease
- Potential contraindications to their clinical use remains elusive
- Parameters for monitoring clinical effectiveness also need to be established and are likely to be disease-specific.
- There is a need for established standards for cell expansion protocols, product quality, and safety controls before national regulatory bodies can begin the task of regulating the area of MSC therapy.
- As mentioned in our previous post on MSCs, ways to prolong the life of injected MSCs in recipient tissue are also needed to make this approach feasible for long-term treatment.
What about MSCs as Research Models?
It’s easy to get caught up in the hype of MSC therapy, but an equally important facet to MSCs is their use in research models. One notable example is the use of MSCs to develop accurate models of sarcomagenesis (tumors of mesenchymal origin). Research has revealed links between MSCs and cancer, and MSCs can inhibit or promote tumor growth depending on their surrounding conditions. Interest in using MSCs to model sarcomagenesis has grown from experiments with transgenic mice and genetic intervention of MSCs that pinpoint MSCs as the most likely cellular origin for certain sarcomas, one of the most aggressive soft tissue tumor types.
Unlike blood-cancers and carcinomas, new therapies for sarcomas are lagging behind, owing largely to the heterogeneity of this tumor type (> 70 different histopathological subtypes), and our lack of knowledge about the molecular events governing transformation and tumor progression. Although the exact chain of events leading to transformation in MSCs is not fully understood, disruption and activation of several tumor suppressor and oncogenic pathways respectively are known prerequisites for sarcomagenesis in human MSCs (4). Although sarcomagenesis is an obvious concern for MSC therapy, it creates an excellent opportunity to unravel the etiology and pathogenesis of mesenchymal cancers, which should reveal novel drug targets and lead to advances in therapies against sarcoma-initiating cells.
3D Tissue Models
Immortalized human MSCs can be used to generate 3D organoids that in theory represent any tissue type, for example, liver, skeletal, brain, and mammary tissue. These organoids can then be used to screen genome-wide mutations and gene deletions, novel drugs, modes of drug delivery, and other parameters as a favorable alternative to animal models. Not only does this allow for circumvention of ethical issues, it may also provide results that are more translatable to human biology, since results gleaned from animal (typically mouse) models are often not a reliable indicator of human physiology.
Bone grafting is necessary for the repair and regeneration of bone damage that occurs following serious fractures in elderly individuals with osteoporosis, certain types of tumor removal, or in individuals with congenital bone disorders. Although autologous grafts are currently seen as the gold standard in this field, bone tissue engineering is being explored as a promising alternative given the limitations of autologous grafting, for example, pain and risk of infection at the donor site, loss of blood, and increased operative time.
Many approaches to bone tissue engineering have relied on the implantation of 3D-cultivated osteoblasts derived from human bone marrow MSCs. Tissues generated using these strategies, however, don’t always possess the desired profile of signaling and regulatory molecules, and as such their function and structure may not accurately reflect the physiological situation. A team of US-based researchers reported a way around this problem in 2016, when they described the differentiation of osteoblasts and osteoclasts from human iPSC-MSCs (MCSs derived from iPSCs) and macrophages upon co-culture on appropriate 3D scaffolds. This approach led to a tissue that manifested both the tissue remodeling process of human bone and the anticipated interplay between bone and immune cells. The result was accelerated bone formation in vitro and the formation of mature bone-like tissue in mice following transplantation with the co-cultured cells (1).
This article aimed to dig into the main two applications for MSCs to date. Stay tuned for future posts where we look into some of less commonly discussed applications for MSCs. If you are studying an aspect of MSC biology not mentioned here or in our introductory post about MSCs, let us know by dropping a line in the comments section!
References and Additional Reading
- Jeon OH, Panicker LM, Lu Q, Chae JJ, Feldman RA, Elisseeff JH. Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. Sci Rep. 2016;6:26761.
- Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-76.
- Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5(3):309-13.
- 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.
- Funes JM, Quintero M, Henderson S, Martinez D, Qureshi U, Westwood C, et al. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc Natl Acad Sci USA. 2007;104(15):6223-8.
Perspective: From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research. 2006. Davor Solter. Nature Reviews Genetics 7 (319–327).
Article by Karen O’Hanlon Cohrt PhD. Contact Karen at firstname.lastname@example.org.
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.