MSC and Cell Therapy
An example that is more relevant for the short term is the use and potential manipulation of mesenchymal stromal cells (MSC). MSC are a promising cell type for cell therapy; these cells can be found in many tissues (bone marrow, adipose tissue, placenta, etc.). MSC have a limited differentiation capacity (as opposed to embryonic stem cells), are immune-quiescent, and it is becoming increasingly evident that in many cases MSC exert their therapeutic function by secretion of cytokines, chemokines, growth factors, etc. The secretome of MSC includes angiogenic factors, anti-inflammatory factors, immune-modulatory factors, antifibrotic factors, and more. But what determines exactly what proteins MSC secrete, and at what quantities? As with most cells, this depends on the environmental conditions in which the cell is present. MSC sense their environment and respond by altering gene expression, protein production, and the protein secretion profile. For example, an MSC placed under hypoxic conditions will in most cases increase the secretion of VEGF, a central angiogenic factor.
Currently, the common practice is for MSC to be harvested from a donor or from the patient, expanded by culturing under conditions deemed to be optimal for cell proliferation (glucose, pH, dissolved oxygen, etc.), collected, and injected to the patient. Once in vivo, it seems that MSC can sense the environment and alter their secretion profile accordingly to aid in healing. Moreover, the cells are continuously adjusting to environmental signals; their secretory profile is dependent on the signals that the cells receive, thus cells will not “oversecrete”. However, this is a battle against time, since in most cases the majority of MSC disappear within several days of delivery; thus, the window for the cells to transform and act in response to the in vivo disease conditions is relatively short.
An alternative concept would be to alter the cells while still in vitro by changing the MSC culture conditions in a way that would “prime” them prior to delivery. By exposing the cells to conditions that cause them to respond in a certain way, for instance growing them in hypoxic conditions to “turn on” their proangiogenic properties prior to injection, we can optimize the cell biology prior to delivery and possibly significantly increase the cell potency and efficacy vis-à-vis ischemic indications. Moreover, by altering cell culture conditions prior to delivery, we may be able to coax cells, by inducing epigenetic changes, to perform functions and to secrete factors which they normally would not perform/secrete.
This example is true for many cell types and therapeutic modalities; by “pushing the cells around” during the in vitro cell culture process cells can be directed down a certain differentiation path, or altered to be less susceptible to immune rejection, or optimized to secrete required factors, and even primed to target a certain organ, all by modulating various aspects of their in vitro culture process. In other words, in cell therapy in many respects “the process is the product”.
The options are almost endless; we may be able to rely on one cell type, form an abundant and ethically acceptable source that could potentially be produced in-mass and at low-cost, to treat multiple diseases. This would be a significant step forward for the fledgling cell therapy industry.