Anyone in the field of regenerative medicine will be aware of the powerful trophic, paracrine and immunomodulatory effects of mesenchymal stem cells (MSCs) (1). To achieve maximum therapeutic benefit, it is important to determine the optimal route for delivering stem cells and to learn about their fate once they are introduced into the body. There are two main modes of stem cell delivery: local delivery into the tissue and systemic delivery (delivery throughout the body). Local delivery includes injection into the bone (2), muscle etc.
In this blog, I will focus on the systemic delivery of stem cells. This mode of delivery has been considered advantageous by many because it is minimally invasive, affords broad biodistribution and ease of access. Systemic delivery can be further classified as intravenous (IV) and intra-arterial (IA).
One of the major difficulties encountered with IV injection of cultured MSCs is that the cells get trapped in the lungs because of their size (20-30 µm in diameter). Due to this phenomenon, also known as the “pulmonary first pass effect”, more cells are required so that the MSCs can reach the injury site distal to the lungs. Whereas, upon IA delivery the cells avoid getting trapped in the lungs at least once and consequently lesser number of cells are required.
One animal study highlights the difference between intravenous and intra-arterial routes of administration of mesenchymal stem cells (MSCs). After injuring only one limb by irradiation, mice were injected either intravenously or intra-arterially with MSCs expressing a marker (reporter gene) and the cells were tracked over time. Upon IV delivery, there was significant entrapment of cells in the lungs whereas upon IA delivery, cells were more evenly distributed throughout the entire animal. Remarkably, after IA delivery, at later times, there was engraftment of cells at the injured limb but not at the non-injured limb. In contrast, in animals injected intravenously, the MSCs were undetectable as early as one week.
Overall, it appears IA delivery of stem cells in animals has certain advantages; by using this route, initial entrapment in the lung is avoided, a smaller number of cells is sufficient thereby reducing the possibility of pulmonary emboli formation that increases mortality and the cells home to the site of injury or inflammation. I would like to mention here that the “smaller number of cells” delivered intra-arterially is still large enough to be clinically challenging while treating humans.
Animal studies that evaluate the fate of MSCs after systemic delivery generally utilize cultured MSCs. Why is this important? If cultured MSCs were delivered to humans, this procedure would go beyond the realm of minimal manipulation and therefore would involve increased regulation by the FDA. In addition, culturing stem cells can potentially alter the properties of the cells, notably their proliferation and differentiation capacities. Whatever the route of administration, it is important to remember that freshly isolated MSCs have better homing capabilities, compared to their culture-expanded counterparts.
The question then is whether systemic injection of autologous fresh bone marrow concentrate (BMC) containing MSCs will yield a sufficient number of cells at the injury site and provide restorative benefit. This cannot be determined at this time and will need to be tested.
Finally, delivering stem cells directly into the afflicted region instead of waiting for cells to home to the injury site would kick start the repair process potentially resulting in better clinical outcomes for the patient. Utilizing an autologous bone marrow concentration device at the point of care, that provides stem cells (whose viability is intact), growth factors, cytokines and platelets that can be directly injected into the injury site is the most logical choice, at least for indications such as osteonecrosis, osteogenesis imperfecta and osteoarthritis to name a few.