Study on MCPH1 Nuclear Transfer Induced by Aging Activating Necrosis and Impairing Hematopoietic Stem Cell Function

Research Background

The aging of hematopoietic stem cells is associated with an increased risk of various blood diseases, and DNA damage is a significant factor driving the aging of hematopoietic stem cells. However, the underlying molecular mechanisms are not fully understood. Recent studies indicate that microcephalin (MCPH1) has different functional roles in the nucleus and cytoplasm of mouse hematopoietic stem cells. It maintains genomic stability in the nucleus and prevents necrosis in the cytoplasm by binding to phosphorylated RIPK3. As aging progresses, MCPH1 shifts from the cytoplasm to the nucleus, reducing its cytoplasmic content, thereby activating necrosis and deteriorating the function of hematopoietic stem cells.

Research Source

This research was conducted by Hanqing He, Yuqian Wang, Baixue Tang, Qiongye Dong, Chou Wu, Wanling Sun, and Jianwei Wang, among others, and is affiliated with the Chinese Academy of Medical Sciences, Tsinghua University, Peking University Shenzhen Hospital, and Xuanwu Hospital of Capital Medical University. The findings were published in the April 2024 issue of the journal Nature Aging.

Research Methods

The researchers used mouse hematopoietic stem cells as the study model. Methods such as competitive transplantation experiments, i vitro proliferation assessment of hematopoietic stem cells, and RNA sequencing analysis were systematically used to explore the functional role of MCPH1 in the aging process of mouse hematopoietic stem cells. Additionally, the interaction between MCPH1 and RIPK3 was investigated through immunoprecipitation experiments, and the ability of MCPH1 to inhibit necrosis was analyzed using mutants.

Main Results

In vitro experiments revealed that the proliferative capacity of hematopoietic stem cells lacking MCPH1 was severely compromised. In in vivo experiments, transferring hematopoietic stem cells with MCPH1 mutations into recipient mice demonstrated a significantly impaired reconstruction capability, along with a tendency to differentiate towards myeloid lineages. RNA sequencing analysis showed that hematopoietic stem cells lacking MCPH1 activated myeloid proliferation genes at the transcriptional level while repressing the expression of hematopoietic stem cell characteristic genes.

Further experiments indicated that the necrosis-preventing role of MCPH1 in hematopoietic stem cells is related to its interaction with RIPK3. MCPH1 binds to RIPK3 via its C-terminal BRCT domain to inhibit its activation. Moreover, as cells age or undergo DNA damage, MCPH1 translocates to the nucleus, leading to the activation of necrosis-related genes in the cytoplasm, significantly increasing cell death in aged cells.

Conclusion and Value

This study provides a new molecular mechanism for the aging of hematopoietic stem cells, specifically the MCPH1-mediated activation of necrosis, offering new insights into the molecular processes behind aging. The revealed dual functional roles of MCPH1 in the nucleus and cytoplasm, as well as the regulatory mechanism of its nuclear transfer, may also apply to other types of stem cells aging and aging-related diseases. This provides new possibilities for developing potential treatments and interventions to delay aging.