Mesenchymal stem cells (MSCs) can be induced to differentiate and express the traits of a diverse range of cell types, including muscle, bone, skin, cartilage, tendons, ligaments, marrow stroma, fat, neural cells, and more. For this reason, MSCs represent a population of cells with the potential to contribute to treatments for a diverse range of acute and degenerative diseases in which tissues need regeneration or repair.
While mesenchymal stem cells have been explored for potential benefits across a wide range of conditions, there are four key areas that represent the majority of investigation to date, which are:
- Osteogenic repair
- Myogenic and myocardial repair
- Neural repair
- Pancreatic repair
In each of these applications, MSCs represent an advantageous cell type for allogenic transplant. As evidence indicates, MSCs are immune-privileged, with low MHC I and no MHC II expression, which reduces risk of rejection and complication during transplantation. [1]
1. Osteochondral Repair
Mesenchymal stem cells are being investigated for use in the treatment of a number of skeletal conditions. The osteogenic potential of MSCs has been utilized to treat defective fracture healing, both alone and in combination with scaffolds, in the repair of large bone defects.[2] This approach has been met with a high degree of success. MSCs have also been used for cartilage repair. In a study conducted by Wakitani and colleagues, autologous MSCs were expanded ex vivo, embedded in a collagen gel, and re-implanted into areas of articular cartilage defect in osteoarthritis patients.[3] It was concluded that formation of hyaline cartilage-like tissue was improved in the experimental group versus the control group.
Although most applications for tissue repair involve local transplantation of MSCs to directly target an area of injury, systemic transplantation of MSCs has been in place for a long time in the form of hematopoietic stem cell transplants. Successful application of systemic MSC transplant has been performed in children with osteogenesis imperfecta. In a study conducted by Horwitz and colleagues, children with osteogenesis imperfecta received systemic infusion of allogenic MSCs. Transplanted MSCs migrated to bone and produced collagen, thus suggesting that mesenchymal stem cells may represent a novel approach for treating this debilitating genetic condition.[4]
Applications of mesenchymal stem cells in orthopedics are on the rise. Currently, the interdisciplinary orthopedics market is sized at U.S. $100 million annually, but it is expected to surpass the $3 billion mark within the next decade.[5] As orthopedic problems ranging from back pain to osteoporosis plague 75 million Americans, or approximately a quarter of the U.S. population, it is apparent that the demand for MSC-based orthopedic treatments will continue to rise. It is anticipated that bio-pharmaceutical[6] and pharma companies will consider development of MSC-based orthopedic therapies a priority area for research and development due to the high valuation of the orthopedics market and its accelerating growth.
2. Myogenic and Myocardial Repair
A number of groups have reported mesenchymal stem cell differentiation into cardiomyocytes in vitro. The current in vivo approach consists of injecting undifferentiated MSCs or whole bone marrow directly into the heart. Although the underlying mechanisms remain to be understood, significant improvement has been observed, suggesting that MSC infusion triggers the formation of new cardiomyocytes and neoangiogenesis in the human heart.[7],[8] However, it is still unclear whether MSCs act directly by in situ differentiation or fusion with resident myocytes[9], or indirectly through secretion of pro-myogenic factors promoting endogenous myocardial repair, such as VEGF and FGF.[10]
3. Neural Repair
The ability of mesenchymal stem cells to migrate to the site of injury has also been reported following transplantation in the brain. MSCs transplanted into rat striata were observed to migrate across the corpus callosum and populate the striatum, thalamic nuclei, and substantia nigra of a lesioned hemisphere.[11] Untreated MSCs systemically infused into animals with damaged brain tissue have also been seen to migrate to the trauma site and improve recovery, although whether this is via secretion of neuroprotective factors or by differentiation into neural tissue remains unclear.
While it is not disputed that the MSCs appear to serve a positive role in recovery, there is debate as to whether the signs of differentiation observed in situ are real or simply a result of cell fusion with resident neural cells. More research is needed to determine the precise extent of MSC contribution in brain repair models, since such results could have implications for neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, and traumatic events such as stroke or spinal cord injury.
Although the adult brain contains populations of neural stem cells, these are insufficient to replace the massive number of cells required to treat these conditions on a functional level.[12] To date, the critical difficulty with treating neurological degeneration, brain defects, and head trauma has been the difficulty of sourcing neural progenitor cells acceptable for use in transplantation. While fetal tissue and differentiated embryonic stem cells have been considered for this purpose, these sources suffer limitations that included limited tissue availability and ethical and safety concerns.
The identification of an adult population of cells, such as mesenchymal stem cells, which can be easily obtained from autologous or donated marrow and can be cultured and manipulated ex vivo, would represent a significant breakthrough in the search for many applications in neuro-regenerative medicine. Because clinical trials impacting the brain are particularly dangerous to perform in humans, thus far most of this research has been performed in animal models.
4. Pancreatic Repair
As mentioned, it has also been demonstrated that MSCs have the potential to differentiate into beta-pancreatic islet cells.[13] Specifically, Chen and colleagues demonstrated differentiation of rat bone marrow-derived mesenchymal stem cells in vitro into functional islet-like cells. This finding represents potential use of MSCs to treat a range of pancreatic-related diseases, including:
- Diabetes
- Pancreatic cancer
- Cystic fibrosis-induced damage of the pancreas (debilitating)
- Congenital malformations of the pancreas
Currently, the U.S. Center for Disease Control (CDC) estimates that approximately 24 million adults in USA have diabetes, mostly type-2 diabetes that is associated with a poor diet and lack of exercise. More frightening, however, is that the CDC projects that a third of the U.S. population will have diabetes by 2050.[14] Therefore, MSC-based treatments for diabetes will likely be a target area for medical research.
FOOTNOTES:
[1] Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol 2006; 36: 2566-2573.
[2] Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A , et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 2001; 344: 385-386.
[3] Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage 2002; 10: 199-206.
[4] 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: 309-313.
[5]Biomed.brown.edu,. ‘Orthopedics’. N.p., 2015. Web. 17 Oct. 2015.
[6] Biopharmaceutical products are pharmaceuticals derived from life forms.
[7] Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: The BOOST randomized controlled clinical trial. Lancet 2004; 364: 141-148.
[8] Fuchs S, Satler LF, Kornowski R, Okubagzi P, Weisz G, Baffour R, et al. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: A feasibility study. J Am Coll Cardiol 2003; 41: 1721-1724.
[9] Lee JH, Kosinski PA, Kemp DM. Contribution of human bone marrow stem cells to individual skeletal myotubes followed by myogenic gene activation. Exp Cell Res 2005; 307: 174-182.
[10] Xu M, Uemura R, Dai Y, Wang Y, Pasha Z, Ashraf M. In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol 2006.
[11] Hellmann MA, Panet H, Barhum Y, Melamed E, Offen D. Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents. Neurosci Lett 2006; 395: 124-128.[12] Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-1438.
[13] Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J of Gastroenterol 2004; 10(20): 3016–3020.
[14] National Diabetes Fact Sheet – Center for Disease Control (CDC). Available at: http://www.cdc.gov/diabetes/statistics/index.htm [Accessed May 11, 2013].