Repairing Cartilage With Fat-Based Stem Cells May Be Feasible With New Technology

Head-to-head comparisons between bone marrow and fat stem cells have shown that bone marrow stem cells consistently outperform fat stem cells. As I have written in past posts, the present protocols for inducing cartilage from mesenchymal stem cells were developed using bone marrow stem cells. Therefore, the fact that bone marrow stem cells outperform fat stem cells with it comes to cartilage formation is no surprise.

In a study in New Zealand White rabbits, bone marrow stem cells outperformed fat stem cells when it came to the repair the cartilage defects in the knee joint. See Li Q, Tang J, Wang R, Bei C, Xin L, Zeng Y, Tang X. “Comparing the chondrogenic potential in vivo of autogeneic mesenchymal stem cells derived from different tissues.” Artif Cells Blood Substit Immobil Biotechnol. 2011 Feb;39(1):31-8. Here again, the system for chondrocyte differentiation system used was developed with, by, and for bone marrow mesenchymal stem cells. Thus the ability of these cells to outperform fat stem cells says nothing about the ability of fat-based mesenchymal stem cells to form cartilage in alternative culture systems.

Because fat-based stem cells are highly accessible and unlikely to be rejected by the immune system, there is a deep desire to efficiently convert fat-based stem cells into cartilage. Unfortunately, this task is not as straightforward as previously believed. As it turns out, fat-derived stem cells secrete molecules that actually inhibit cartilage formation. However, new research has found that if fat-based stem cells are pre-treated with antibodies that neutralize Vascular Endothelial Growth Factor (VEGF) and growing them in nutrients that are specifically designed to promote cartilage formation can counteract the effects of these molecules.

Chondrocytes make and maintain healthy cartilage. However, damage and diseases, such as osteoarthritis, can destroy cartilage and this can result in pain, compromising the patient’s mobility.

Professor Barbara Boyan, and her colleagues from the Georgia Institute of Technology showed that adipose (fat) stem cells (ASCs) secrete large amounts of factors. Some of these factors, especially the growth factor VEG, prevents cartilage regeneration and actually causes the death (apoptosis) of chondrocytes.

However, by treating ASCs with a media designed to encourage the differentiation of fat-based stem cells into cartilage cells reduced the amount of these secreted factors and prevented the growth of blood vessels. Also, the fat-based stem cells were treated with an antibody that neutralizes VEGF, and this pretreatment prevented chondrocyte death.

Professor Boyan said: “Non-treated ASCs actually impeded healing of hyaline cartilage defects, and although treating ASCs improved the situation they added no benefit compared to cartilage allowed to heal on its own. However we only looked at cartilage repair for a week after treatment. Other people have shown that two to six weeks is required before the positive effect of ASCs on cartilage regeneration is seen.”

Therefore, fat-based stem cells might be able to help repair damaged cartilage, and careful handling plus pre-treatment can help ensure a positive result.

See: “Adipose stem cells can secrete angiogenic factors that inhibit hyaline cartilage regeneration,” Christopher SD Lee et al.; Stem Cell Research & Therapy, 24 August 2012, 3:35, DOI:10.1186/scrt126

New York Researchers Find Signaling Link Between Pluripotent Stem Cells and Cancer

Stem cell researchers at Mount Sinai School of Medicine, the University of Manchester and the MD Anderson Cancer Center have discovered a new role for signaling pathways usually associated with cancer cells in embryonic stem cell self-renewal and in adult cells that are in the process of being reprogrammed into induced pluripotent stem cells (iPSCs).

Normal cells have several genes known as “proto-oncogenes” that stimulate cell growth and cell proliferation. When expressed, proto-oncogenes drive cells to grow, and mutations in proto-oncogenes that disrupt their regulation convert them into “oncogenes” that drive cells to grow uncontrollably. Oncogenes are commonly found in tumors and the accumulation of oncogenic mutations in cancer cells drive them to grow faster and faster and with less and less controls.

In this publication, a proto-oncogene called Aurka and its role in embryonic stem cell self-renewal was examined. Aurka is commonly amplified in several human cancers, which underscores its importance in driving growth.

By utilizing a functional genomics strategy, the research group identified the protein kinase Aurora A or Aurka as a vital component of embryonic stem cell function. Aurka is a protein kinase, which is a biochemical way of saying that it is an enzyme that places phosphate groups on proteins. By placing phosphate groups on proteins, Aurka regulates their function. One of the main targets is a well-known tumor suppressor gene product called p53. Tumor suppressor genes encode proteins that put the brakes on cell proliferation. Tumors tend to accumulate loss-of-function mutations in tumor suppressor genes and these mutations decrease the controls on cell proliferation. The p53 tumor suppressor protein is known as the “guardian of the genome.” Mutations in p53 are found in a very wide range of tumors and many oncologists think that inactivating mutations in the p53 gene are mandatory for the evolution of cancer.

In the absence of Aurka, p53 activity is up-regulated and up-regulation of p53 in embryonic stem cells causes them to differentiate and lose their undifferentiated state. However, If Aurka is active, it attaches a phosphate group to p53 and inhibits it, thus shifting the embryonic stem cell to a self-renewal state.

Ihor R. Lemischka, the Lillian and Henry M. Stratton Professor of Gene and Cell Medicine and Director of the Black Family Stem Cell Institute at Mount Sinai Medical Center in New York City, said: “These studies are exiting not only from a basic science point-of-view, but also because they suggest that stem cell research may impact the development of novel treatments for cancer. Conversely, cancer research may facilitate the realization of the biomedical potential of stem cells.”

Mature cells have low levels of p53, but embryonic stem cells and iPSCs show high levels of p53. The p53 protein also has a limited role in promoting programmed cell death. They also inhibit the cell cycle in pluripotent cells and these recent findings provide a possible explanation to my pluripotent stem cells have so much of this protein even though it is relatively inactive.

By developing Aurka inhibitors, these researchers hope to treat cancers more effectively, and also manipulate pluripotent stem cells more successfully.

See “Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling,” Dung-Fang Lee et al., Cell Stem Cell, Volume 11, Issue 2, 179-194, 3 August 2012 DOI:10.1016/j.stem.2012.05.020.