RESEARCH

Tissue stem cells in aging and regenerative medicine

Tissue stem cells in aging and regenerative medicine

Self-renewal is an incredible cellular ability found only in stem cells. With the self-renewing potential, a stem cell can maintain an entire tissue with elaborate functions for a lifetime, such as blood, gut, skin, skeletal muscle — you name it.
Because stem cells are multi-potent, tissue stem cells can produce specialized cells that are required for the given tissue to function properly. For example, blood stem cells (or hematopoietic stem cells) can generate all kinds of blood cells found in the human body; these include, but are not limited to, red blood cells (erythrocytes) for oxygen distribution, platelets for blood coagulation, B- and T- lymphocytes for acquired immunity, and granulocytes and macrophages for innate immune responses. These cells are generated at high rates to replace old blood cells. Each day, 100 billion white cells, 200 billion red cells and 400 billion platelets are being produced. Collectively, it is almost a trillion per day, and all of these cells can originate from a single hematopoietic cell! Even more surprisingly, the massive cell production can last a lifetime because hematopoietic stem cells can generate themselves and increase their numbers without losing their multipotency, which we call self-renewing potential.
Because self-renewing stem cells can provide as many “functional” cells as needed, they not only maintain functioning tissues but also help to repair damaged tissues after injury. When we have a cut, platelets stop bleeding, immune cells prevent infections, and the cut is sealed to initiate the skin repair process. Dead cells are removed and new skin cells (keratinocytes) generated from epidermal stem cells start to populate the site of injury and eventually healing the wound. It would be very hard to survive if there was no way to repair damage after tissue injury. Also, as we get older, the capability of stem cell self-renewal declines in many tissues. Therefore, our stem cells’ ability to repair and regenerate is also essential for us to live a long and healthy life. In our lab, we study how self-renewal is regulated in tissue stem cells.

Cancer, stem cells and cancer stem cells

Cancer, stem cells and cancer stem cells

As discussed above, stem cells are important players in our health and well-being, and their ability to self-renew is a key property for robust tissue function and repair. The studies in the past few decades, however, have revealed that the ability to self-renew is a double-edged sword. We now know that cancer cells often mis-utilize the self-renewal potential to proliferate and maintain themselves in our body for a long time. Some cancer cells also acquire stem cell-like properties and become resistant to radiation or chemotherapies. These types of cancer cells are often called “cancer stem cells” because they behave like stem cells in tumor tissues. Cancer stem cells are also responsible for metastasis to a remote or secondary organ as well as relapse after therapy in many types of human cancers. Therefore, self-renewal is not always a good thing and can be a target of malignant transformation leading to cancer development. Here we have several questions- are the same molecular systems used in healthy tissue stem cells and cancer for self-renewal? Can we find any differences between them? Could we molecularly take aims at these differences for the development of safe and effective therapeutic strategies to promote regeneration in healthy stem cells or cure aggressive cancers? These are the core research questions we are asking, and we’re working hard to find the answers.

Metabolic regulation of cell fates in cancer

Metabolic regulation of cell fates in cancer

We are beginning to understand that both stem cells and cancer show distinct cellular metabolism compared with mature normal cells. Previous studies have shown that the “metabolic reprogramming” is important for cell growth and adaptation to their microenvironment. In cancer, such altered metabolism often leads to dependency on specific nutrients, and therefore, targeting cancer-specific metabolism would be an effective therapeutic strategy. To push to this goal, it is essential to identify metabolic “weaknesses” in human cancer. Recently we found that the branched-chain amino acid (BCAA) metabolism is specifically activated in and essential for myeloid leukemia. To make a long story short, we discovered that BCAT1, a cytosolic BCAA transaminase, regulates how cancer cells behave by promoting BCAA production in leukemia cells. The most exciting part of our finding is that the cancer stem cells need BCAT1 function to self-renew and proliferate, and therefore, inhibiting BCAT1-BCAA pathway may constitute an effective therapeutic target in human myeloid leukemia.

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