The "Paracrine Effect" is the best thing about Stem Cells

Ian Rogers, PhD,
scientist at the Samuel
Lunenfeld Research Institute,
Toronto, Canada

Regenerative medicine is the science of repairing diseased and damaged cells or tissues. This can be accomplished in two ways. First, stem cells can directly replace the diseased cells by engrafting and differentiating into the required cell type. This is what happens during a bone marrow transplant, where the donor stem cells replace the patient's blood and immune system.

The second method of regenerative medicine is the paracrine effect. In this mechanism some of specialized donor cells act to stimulate the patient's cells to repair the diseased tissue, without the donor cells contributing directly to the new tissue. This happens because the donor cells secrete factors that signal the patient's cells to change their behavior, and this signaling from one cell to another is called the paracrine effect.

In many pre-clinical studies of stem cell transplants, investigators observed that damaged patient tissue was repaired after the transplant, but when the new tissue was analyzed there was a noticeable absence of donor cells. Upon further investigation, scientists were able to demonstrate that the donor stem cells were secreting factors that triggered the patient's cells to repair the tissue themselves. Mammals have a wound repair mechanism that on its own can only deal with small wounds, and is incapable of repairing large wounds or of regenerating new functioning tissue instead of just scar tissue. But, studies of the paracrine effect have demonstrated that mammalian tissue does contain cells capable of regeneration, they just need to receive the appropriate signals to initiate the regeneration and repair.

The paracrine mechanism has turned out to be very beneficial. At first, most scientists were disappointed that transplanted donor cells often did not contribute directly to new tissue, but the advantages of having a paracrine effect soon became apparent. The most important observation was that even though the donor cells were short lived, they had a long term effect on tissue regeneration. It seems that they are important for initiating tissue repair but are dispensable once the patient's cells are activated.

The fact that donor cells do not have to persist in order to achieve a cure via the paracrine effect has the implication that unmatched donor cells can be used. The unmatched cells will survive for 1-2 weeks in a patient before they are rejected, and this is enough time for the cells to initiate tissue regeneration. By dispensing with the need to find matched donor cells, therapies that rely on the paracrine effect are open to many more patients.

Many different cell types can invoke a paracrine response. Paracrine effect cells include mesenchymal cells and blood cells that can be isolated from donor bone marrow, adipose (fat) tissue, umbilical cord blood, and umbilical cord tissue.

In addition, studies have indicated that the paracrine effect is amplified because the donor cells are attracted to the damaged tissues that need their help. The damaged patient cells are secreting cytokines, regulatory proteins that act as mediators to generate an immune response that attract the donor cells. In turn, the donor cells secrete their own cocktail of proteins that stimulate the patient's stem cells and help to reduce inflammation, promote cell proliferation, and increase vascularization and blood flow into the areas that need to heal. Paracrine effect cells can also secrete factors that inhibit the death of patient cells due to injury or disease.

An important third paracrine effect is their ability to 'dampen' the immune response that occurs during transplant rejection or during autoimmune disease (1). In this case the cells can be used directly or in conjuction with other stem cells for therapeutic purposes. For example, the application of mesenchymal cells along with blood stem cells during a bone marrow transplant seems to reduce graft versus host disease (2).

An advantage of using cells, versus medication, to promote regeneration is that transplanted cells will respond to their environment and secrete the factors as they are needed and in the appropriate concentration. The cells can be thought of as 'drug factories' that adapt as the tissue is repaired. Preclinical studies have demonstrated the efficacy of mesenchymal cells and cord blood cells for the treatment of neural, heart, kidney and muscle based diseases. There have been some convincing studies on the neuroprotective effect of cord blood cells. In one study, cord blood cells were used to treat spinal cord injury. The transplanted cells were only present for 7-10 days, but were able to reduce the wound lesion and significantly improved mobility in the hind limb of spinal cord injured rats when compared to injured animals that did not receive cord blood cells (3). Recently a study showed that cord blood could reduce diabetes-related kidney damage. The improvement was significant although very few cord blood cells engrafted, indicating that the mechanism of action was via the paracrine effect (4). Myocardial damage has also been reported to be repaired by the paracrine effect of cord blood (5).

The paracrine effect was an unexpected mechanism for tissue regeneration from stem cells but has led to new possibilities for the treatment of different diseases. The ability of umbilical cord blood and tissue-derived stem cells to promote tissue regeneration by both contributing directly to new tissue as well as by the paracrine effect of stimulating endogenous repair will lead to novel cell therapies.

Dr. Ian Rogers is an associate scientist in the Research Centre for Women's and Infants' Health at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto, Canada. He is also an assistant professor in the Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto. Dr. Rogers was involved with the establishment of Canada's first, and largest, cord blood bank, originally located at Mount Sinai Hospital and now managed by Insception Biosciences. His research interests include cell differentiation, cell-cell signaling, and the simple and complex three-dimensional organization of cells into functional organs and tissues. Dr. Rogers is on the Advisory Panels of the Coalition for Regenerative Stem Cell Medicine, and the Parent's Guide to Cord Blood Foundation.

References

1. Najar, M., et al. Adipose-tissue-derived and Wharton's jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue engineering. Part A 16, 3537-3546 (2010).
2. Lazarus, H.M. Acute leukemia in adults: novel allogeneic transplant strategies. Hematology 17 Suppl 1, S47-51 (2012).
3. Chua, S.J., et al. The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa 1976) 35, 1520-1526 (2010).
4. Park, J.H., Park, J., Hwang, S.H., Han, H. & Ha, H. Delayed treatment with human umbilical cord blood-derived stem cells attenuates diabetic renal injury. Transplantation proceedings 44, 1123-1126 (2012).
5. Greco, N. & Laughlin, M.J. Umbilical cord blood stem cells for myocardial repair and regeneration. Methods Mol Biol 660, 29-52 (2010).