The coexistence of two seemingly opposing features - self-renewal and differentiation - distinguishes stem cells from most other cells. This ability empowers stem cells to grow and to regenerate tissues, a quality that is particularly apparent in the blood, where millions of cells are lost every day and stem and progenitor cells tirelessly produce erythrocytes, thrombocytes, myelocytes, and lymphocytes. Conversely, when stem cell function decreases, it necessarily has an impact on tissue regeneration. Aging is an impairment that affects everyone. The decline of hematopoietic stem cell activity over time results in a reduced recovery from blood loss and a weakened immune system. In particular, the crucial balance between self-renewal and differentiation appears to be disturbed in aged stem cells. The maintenance of this dualism is achieved by opposing molecular forces. On one hand, the preservation of multilineage potential depends on a hyperactive genome that is easily turned on. On the other hand, the preservation of an undifferentiated state depends on silencing mechanisms that allow stem cells to maintain their quiescent composure. Transcriptional noise is reduced on multiple levels in stem cells: transcriptional repressors, epigenetic factors, and RNA inhibition are all collaborating in an effort to prevent premature differentiation. But what if a signal sneaks through? Indeed, all the aforementioned regulators affect RNA levels. However, it is naive to assume stem cells would not possess yet another level of repression if RNA were to be translated into its final product: proteins. Certainly, a considerable fraction of the genome encodes factors that are devoted to the elimination of proteins. This vast group of molecules, the ubiquitin-proteasome system (UPS), represents the final potential silencing layer, able to eliminate products of accidentally activated genes. Interestingly, the UPS is directly involved in aging processes in several organisms and tissues. In spite of this, remarkably little is known about how the UPS regulates the activity and the aging of hematopoietic stem cells. The goal of this research study is to shed light on mechanisms by which protein degradation regulates developmental processes and aging in hematopoietic stem cells. Specifying these mechanisms will provide us with insights into how stem cells operate. Moreover, this knowledge might prove useful for future applications in regenerative medicine.

Public Health Relevance

Stem cells hold great promise for use in regenerative medicine. The proposed research aims at better understanding how stem cells repair and renew tissue and why their function declines with age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
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Kohanski, Ronald A
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Massachusetts General Hospital
United States
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