In September 2009,The Regenerative Medicine Institute began work on the development and application of disease specific autologous stem cell therapy solutions using adipose-derived adult autologous stem cells.
At the time research pointed to autologous cells having an advantage over allogeneic cell transplants, specifically in that the risk of either rejection, or graft vs. host disease was either minimal or null in the case of autologous cells, while it was believed that this was not the case for allogeneic transplants.
Based on this premise, we spent the next few years developing 27 disease specific research protocols and submitting them for both IRB and government approval, with the intention of conducting a series of parallel clinical trials in order to prove the safety of stem cell infusions in each of these conditions.
Through experience we learned that not every condition can be treated as successfully as others. During our research and in the running of a few of these trials we experienced great successes, which garnered recognition and praise from peers and critics alike, including two national research prizes in cardiology for our work in the implantation of adipose-derived autologous stem cells directly into the myocardium of the left ventricle using a novel catheter delivery system, which also served to help us discover just how effective these cells can be.
However, during this time we collaborated with various research institutions and continued to gather information from various sources regarding stem cells, in essence trying to learn as much about them as possible, regardless of whether the information obtained was pertinent to our research or not. It was because of this that we came to learn more about the way stem cells behave and how we were achieving the results we had observed up until then in our trials.
Initially, it was hypothesized that stem cells implanted directly into tissue would almost immediately recognize the cell-surface markers of the tissue it was implanted in, and by contiguity (direct contact with the tissue) distinguish the specific tissue, and whether or not this tissue was damaged to the point where cells needed to be recruited through the production of cytokines in order to initiate repair, or if the tissue had to be replaced altogether through the differentiation of the stem cell itself.
The main factor that casts doubt on this hypothesis was the fact that in many cases the process was inordinately slow. It would take months for patients to show positive and measureable results. And while in most cases these results are still present long-term (as is the case for most congestive heart failure patients), in some cases the positive effects waned, and were shown to be less impressive in conditions where an immune response was involved. However there were exceptions. In cases that involved a decrease in overall perfusion, as is the case in critical limb ischemia and ischemic congestive heart failure, angiogenesis (growth of new blood vessels) was an early indication of improvement and occurred rather quickly.
Through further research and collaboration, we learned that the reason for the delay in tissue regeneration was a previously overlooked activity of the stem cells themselves, which was immune-regulation. It has been shown that MSCs (mesenchymal stem cells) assist via paracrine mechanisms and modulate the regenerative environment via anti-inflammatory and immune-modulatory mechanisms. In response to inflammatory molecules such as interleukin-1 (IL-1), IL-2, IL-12, tumor necrosis factor-α (TNF-α) and interferon-gamma (INF-γ), MSCs secrete an array of growth factors and anti-inflammatory proteins with complex feedback mechanisms among the many types of immune cells.,,,,,
The significance of these findings in for our research and the future of our program cannot be understated. It was this realization that leads us to question what the purpose of such an effect was before beginning the actual repair of tissue. The answer came in a roundabout way. Through our collaboration with several immunologists as well as molecular biologists, we began to explore the idea of the “stem cell niche”, which explains why they are able to thrive in the environment in which they are produced, replicate and thrive before actually being activated and called upon to repair tissue.
Stem cell populations are nowadays shown to be established in “niches” - the specific anatomical locations constituting the microenvironment that is believed to regulate tissue generation, maintenance and repair. Recent evidences point out “that niche saves stem cells from depletion while protecting the host from over exuberant stem cell proliferation”,,,,,,
Once the concept of the “niche” was introduced into our view of how stem cells act in their new environment, we set about finding ways of either accelerating this process, or providing it prior to the implantation of the stem cells in order to allow them to engage the target tissue faster and be able to more efficiently repair it, thereby providing faster results and more noticeable improvement in patient’s quality of life, as well as measurable parameters of their specific conditions.
Due in large part to this fact, in 2013 we asked Dr. Hector Zepeda to join the RMI team. His more than 20 years of experience in innate and adaptive immunology, as well as his experience at the Pasteur Institute and the Karolinska Institute, provided the basis for the development of RMI’s newest form of therapy, for which we’ve created and patented “T Cell Modulator” or TCM®. T Cell Modulator (TCM®) is a leukocyte extract manufactured by a proprietary methodology, described in part in the Patent Cooperation Treaty application # PCT/MX2012/000084. Therapeutic effects of TCM have previously been demonstrated in immunologically mediated conditions, as well as oncology.
TCM® has been shown to act directly upon Toll Like Receptors, which has shown to be an important factor in protecting stem cells in their new environment, as well as promoting their function. “In response to TLR stimulation human AD-MSCs induce the expression of manganese superoxide dismutase (MnSOD), a key protective protein against oxidative stress in the mitochondria. It has been reported that induction of MnSOD protects cells from oxidative stress leading to increased survival. In the settings of an inflammatory response, immune cells release vast amounts of reactive oxygen species which results in the generation of an oxidative milieu. Based on these data we speculated that increased expression of MnSOD by MSCs in response to TLR ligand exposure would provide them with improved engraftment or survival at injured or inflamed sites, leading to enhanced therapeutic effects. ” (O. DelaRosa)
We believe that combining TCM with Stem Cell therapies will provide our patients not only faster and more lasting results, but that the overall impact on general health will be one of improved immune responses, as well as faster and more efficient tissue repair and regeneration. This new and improved program is now available at our new outpatient facility, as well as in Angeles Hospital in Tijuana.
The advantage of this novel combination of therapies is the fact that only one stem cell infusion is required, and a few months of TCM home-based therapy will not only speed up the process, but also help maintain a steady pace of improvement, and provide lasting results.
Iyer S, Rojas M. Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies. Expert Opin Biol Ther 2008; 8: 569–582
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8: 726–736.
Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S et al. Stem cells and cell therapies in lung biology and lung diseases.Proc Am Thorac Soc 2011; 8: 223–272.
Yagi H, Soto-Gutierrez A, Kitagawa Y. Bone marrow mesenchymal stromal cells attenuate organ injury induced by LPS and burn. Cell Transplant 2010;19: 823–830.
Guan X-J, Song L, Han F-F, Cui Z-L, Chen X, Guo X-J et al. Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 2013; 114: 323–335.
Sujata L., Chaudhuri S. Stem Cell Niche, the Microenvironment and Immunological Crosstalk. Cell Mol Immunol. 2008;5(2):107-112.
Scadden DT. The stem-cell niche as an entity of action. Nature. 2006;441:1075-1079.
Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science. 2001;294:2542-2545.
Xie T, Spradling AC. A niche maintaining germ line stem cells in the drosophila ovary. Science. 2000;290:328-330.
Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006; 116:1195-1201
Internet tend to repeat predefined chunks as necessary, making this the first true generator on the Internet.
Powell K. It’s the ecology, stupid! Nature. 2005;435:268-270.
Büscher, “Toll-like receptor-mediated signaling in human adipose-derived stem 14cells: implications for immunogenicity and immunosuppressive potential,” Tissue Engineering Part A, vol. 15, no. 7, pp. 1579–1589, 2009.
M.-F. Tsan, R. N. Clark, S. M. Goyert, and J. E. White, “Induction of TNF-α and MnSOD by endotoxin: role of membrane CD14 and Toll-like receptor-4,” American Journal of Physiology, vol. 280, no. 6, pp. C1422–C1430, 2001.
Büscher, “Toll-like receptor-mediated signaling in human adipose-derived stem 16cells: implications for immunogenicity and immunosuppressive potential,” Tissue Engineering Part A, vol. 15, no. 7, pp. 1579–1589, 2009.