Immunosuppressive Pericytes as Transplantable Natural Ancestors of Mesenchymal Stem Cells
Most adult tissues contain stem cells specialized in their own regeneration and repair (i.e, blood, skin, gut, bone stem cells and many others). In addition, adult organs host a separate subset of stem cells endowed with the broad potential to differentiate into bone, cartilage, fat and muscle, and also indirectly support tissue regeneration via molecular interactions. These mesenchymal stem cells (MSC) have other interesting characteristics in the perspective of applications in regenerative medicine: MSC can be harvested from easily accessed tissues, such as placenta, umbilical cord and fat, and are able to inhibit the immune system. For instance, the severe, and often deadly, immune attack named graft-versus-host disease, elicited in recipients of allogeneic (from a genetically non-identical donor) bone marrow cells, can be completely abrogated if MSC from the host are co-transplanted with the donor bone marrow. MSC are therefore attractive stem cells for allogeneic transplantation, since they are likely not to be rejected and efficiently mediate tissue regeneration. MSC are however elusive cells that have long escaped direct identification; harvested exclusively after long-term culture of their tissue of origin, MSC may undergo genetic alterations and give rise to tumors after transplantation. The normal counterparts, in intact tissues, of MSC have been recently identified as pericytes, which are cells which closely encircle small blood vessels. Interestingly, cultured pericytes, similar to MSC, were found to inhibit immune responses, suggesting that this unique potential natively exists in these cells. The aim of the present project is to determine whether non-cultured pericytes, as they appear just after being isolated from human organs, can already inhibit immune responses. To this end, immune suppression by freshly purified pericytes will be tested in culture. If, as we expect, pericytes represent a novel population of naturally immunosuppressive cells, we shall document the molecular control of this property. Finally, the acceptance of transplanted pericytes will be tested in mouse models in which we will use these cells to regenerate diseased muscle, kidney and heart.
In conclusion, if we meet our goals, we shall document the existence in human organs of a novel population of cells possessing, simultaneously, multi-tissue stem cell potential and immunosuppressive ability. These cells could be purified to homogeneity and transplanted into allogeneic recipients after minimal manipulation, notably avoiding – or keeping to a minimum – in vitro expansion.
We have recently identified in multiple human organs a rare but potent population of multi-purpose stem cells and we propose in the present project to demonstrate that these cells are immunosuppressive, which means that they could be transplanted from a donor into a patient without being rejected. We believe that this project is precisely the type of cutting-edge, original and ethical stem cell research that Californians imagined when they approved proposition 71 in 2004. The establishment of CIRM has transformed the research infrastructure at [REDACTED], and attracted the attention of scientists from other disciplines - for instance, immunology - to this new field. Supporting the demonstration of the existence of an ubiquitous and potentially immunosuppressive stem cell population in human organs would be undoubtedly positive for the public image of CIRM, and would produce intellectual property that would be owned by [REDACTED]. Regarding the potential medical applications of the proposed research, mesenchymal stem cells, of which we propose to characterize the easily transplantable ancestor, would be for instance indicated for the repair and regeneration of bone and cartilage, targeting in particular the large population of elderly people in California. Unfortunately, a large fraction of the aged population suffers from osteoporosis. In 1998, the health care burden for osteoporosis exceeded $2.4 billion in California alone, 64% of this sum being related to hip fracture. Promoting the repair of both normal and healing-impaired bone in an effective manner would reduce the long term health care burden for California’s public health insurance program. Besides direct health cost, bone injuries and diseases can result in hospitalizations and long term disabilities. But the cells on which we are focusing our efforts may offer very promising therapeutic solutions in even more devastating diseases. We have illustrated in our proposal the potential interest of these cells to cure acute renal failure, which is a dramatic consequence of anti-cancer chemotherapies, and heart failure consecutive to myocardial infarction. Improving the use of mesenchymal stem cells in human medicine may therefore dramatically refine the treatment of currently fatal diseases; it will also help reduce the loss of work productivity, lessen work disability costs, and consecutively minimize spending of state income tax.