Immunomodulatory Properties of Wharton's Jelly MSCs: Myth, Reality, and Hidden Potential
When someone thinks to the potential of regenerative medicine, the main idea is that of immature cells which may transdifferentiate towards a mature cell type, which may be used to repopulate a target organ cells, and thereby treat human diseases. This concept drives a lot of research undertaken worldwide.
Wharton's jelly mesenchymal stem cells (WJ-MSC) are not an exception to this rule: They are derived from the tissue constituting the bulk of the umbilical cord (1). Applications of these cells, often supported by data from several in vivo models, range from the nervous system to the liver, pancreas, heart and other organs in the body (2-4).
Usually when stem cells from a donor (allogeneic) are transplanted - or differentiated cells derived from donor stem cells - they are subjected to the same immune restrictions which regulate organ transplantation: often the use of mmune suppressants is mandatory, and then part of the real advantages of stem cell therapy over whole organ transplantation are lost.
However, MSCs feature unusual properties when they interact with immune system cells. Several literature reports have highlighted that MSCs are able to modulate the activity of immune cells, and in particular lymphocytes, by means of several mechanisms, e.g. by secreting molecules which find receptors on lymphocytes, or by direct cell-cell interactions (5). These abilities are promising for cell therapy for a number of reasons. Moreover, they are not limited to bone marrow-derived MSC, which constitute the prototype of all other MSCs, but are particularly prominent in perinatal stem cells, i.e. those cells which are derived by perinatal tissues such as placenta, umbilical cord, and umbilical cord blood (6,7).
The main reason these perinatal MSC have an advantage is the environment in which perinatal tissues develop. In fact, the human fetus represents a semi-allogeneic entity for the mother, which her immune system naturally tends to fight. To overcome this natural rejection, and let the pregnancy get to term, placental cells are able to express several molecules, both secreted or located in the plasma membrane, that have immunomodulatory properties. The activity of these molecules create an environment of peripheral tolerance towards the fetal tissues.
In our experience with WJ-MSC, we strongly believe that these cells maintain a sort of "positional memory" even when grown ex vivo (8). This allows them to continue expressing molecules with immune-modulating activity after they are extracted from their tissue of origin, namely the umbilical cord, and expanded under tissue culture conditions. Even more exciting, they seem to be able to pass on this ability: Very recent reports on MSC from both Wharton's jelly and from amniotic membrane suggest that expression of immunomodulatory molecules is not limited to the undifferentiated parent stem cells, but is also featured in their differentiated progeny.
Prior to the recent boom of studies on immune modulation by MSCs (in the last 6-7 years), the only immune-related markers which were (sometimes) evaluated following differentiation were type I and type II MHC, namely HLA-ABC and HLA-DR. In fact, undifferentiated MSCs express low to medium levels of human leukocyte antigen (HLA) Class I and low levels of HLA Class II to avoid recognition by the immune system (5). In our opinion, the most relevant studies on this topic came out in the last year: The Australia-based group of Manuelpillai explored the maintenance of immune modulation of human amniotic membrane cells when they differentiated towards hepatocytes (9). Our group in Italy investigated the maintenance of various immunomodulatory molecules in WJ-MSCs when they differentiated towards osteoblasts, chondrocytes and adipocytes (10). The molecules we looked at were non-classical type I MHCs (such as HLA-E) and CD276, which we were the first to describe in WJ-MSCs (10).
But why is the maintenance of the immunomodulatory features such a crucial advantage of MSC from perinatal tissues? It is important because it enables the infused donor cells, whether differentiated or not, to engraft into the diseased target organ and positively modify its microenvironment to promote repopulation. Some diseases for which cell therapy has been proposed, such as liver fibrosis or type I diabetes, derive from previous conditions where one or more immune-related processes have caused damage in the organ (chronic inflammation in the liver, pancreatitis in the pancreas) (11). These processes may have exhausted the local population of progenitor stem cells that would normally ensure the regeneration of the functional cells of the organ (12). Therefore, the infusion of immunomodulatory MSC provide a significant advantage by better overcoming host responses, providing the needed functional bridging action, and modifying the underlying pathological conditions at the basis of disease.
In the case of diabetes, our group is exploring co-transplantation of both pancreatic islets and WJ-MSCs in animal models. Our goal is to achieve, in vivo, both the expression of differentiated functions (e.g. insulin production) and immunomodulatory activities (e.g., molecules that suppress inflammation or protect newly generated endocrine cells from immune system attacks).
We hope that our studies and others will let us better understand the hidden potentials of WJ-MSCs, which hold a lot of promise for the regenerative medicine field. A greater understanding of the bioactive components secreted by undifferentiated and differentiated stem cells will enable a more informed use of these cells and their therapeutic derivatives to target specific diseases.
- Corrao S, et al. Umbilical cord revisited: from Wharton's jelly myofibroblasts to mesenchymal stem cells. Histol Histopathol. 2013; 28(10):1235-44 PubMed PMID: 23595555.
- Anzalone R, et al. New emerging potentials for human Wharton's jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity. Stem Cells Dev. 2010; 19(4):423-38. PubMed PMID: 19958166.
- Vawda R, Fehlings MG.Mesenchymal cells in the treatment of spinal cord injury: current & future perspectives. Curr Stem Cell Res Ther. 2013; 8(1):25-38. PubMed PMID: 23270635.
- López Y, et al. Wharton's jelly or bone marrow mesenchymal stromal cells improve cardiac function following myocardial infarction for more than 32 weeks in a rat model: a preliminary report. Curr Stem Cell Res Ther. 2013; 8(1):46-59. PubMed PMID: 23270633.
- Murphy MB, et al. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013; 45:e54. PubMed PMID: 24232253.
- Taghizadeh RR, et al. Wharton's Jelly stem cells: future clinical applications. Placenta. 2011;32 Suppl 4:S311-5. PubMed PMID: 21733573.
- La Rocca G, Anzalone R. Perinatal stem cells revisited: directions and indications at the crossroads between tissue regeneration and repair. Curr Stem Cell Res Ther. 2013; 8(1):2-5. PubMed PMID: 23452028.
- La Rocca G, et al. Novel immunomodulatory markers expressed by WJMSC: an updated review in regenerative and reparative medicine. Open Tissue Eng Regen Med J 2012; 5:50-8.
- Tee JY, et al. Immunogenicity and immunomodulatory properties of hepatocyte-like cells derived from human amniotic epithelial cells. Curr Stem Cell Res Ther. 2013; 8(1):91-9. PubMed PMID: 23270634.
- La Rocca G, et al. Human Wharton's jelly mesenchymal stem cells maintain the expression of key immunomodulatory molecules when subjected to osteogenic, adipogenic and chondrogenic differentiation in vitro: new perspectives for cellular therapy. Curr Stem Cell Res Ther. 2013; 8(1):100-13. PubMed PMID: 23317435.
- Anzalone R, et al. Wharton's jelly mesenchymal stem cells as candidates for beta cells regeneration: extending the differentiative and immunomodulatory benefits of adult mesenchymal stem cells for the treatment of type 1 diabetes. Stem Cell Rev. 2011; 7(2):342-63. PubMed PMID: 20972649.
- Mansilla E, et al. Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes? Stem Cells Int. 2011;2011:943216 PubMed PMID: 21716667.