Role of CD38 in aging and rejuvenation of Hematopoietic stem cells

• Applicant: Dr. Tatyana Grinenko
• Subject Area: Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423821330

The rare population of hematopoietic stem cells (HSCs) resides in the bone marrow and continuously produce all mature blood cells. Upon aging HSCs functionality is gradually declined. This often leads to anemia, lymphopenia, and increased production of myeloid cells. Increased rate of self-renewal division and decline in differentiation capacity of aged HSC can be the reason for increased frequency of malignant disorders of the hematopoietic system with aging. The changes of aged HSCs can be intrinsic or driven by changes in the bone marrow niche where they reside. Unfortunately, the mechanisms of HSC senescence are still poorly understood. In our preliminary work, we found that expression of the ecto-enzyme CD38 increased with aging on HSCs and is correlated with a decrease in mitochondrial functionality. Recently, it was shown for muscle stem cells that increased expression level of CD38 upon aging leads to a reduced amount of nicotinamide adenine dinucleotide (NAD), which is crucially important for mitochondrial function. Inhibition of CD38 or restoration of NAD levels rejuvenates muscle stem cells. Our preliminary work shows that pre-treatment of old hematopoietic cells with specific CD38 inhibitor restored balanced production of mature blood cells, suggesting a possible rejuvenation of old HSCs. Therefore, in my proposal I am planning to investigate the role of CD38 during HSCs aging. I will develop in vitro as well as in vivo methods for slowing down HSC aging or even inducing their rejuvenation. This work will help to increase the life quality of elder people and can help to reduce the frequency of age-associated hematopoietic disorders.

• DFG Programme: Research Grants