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Updated: Dec 21, 2025
11:06
Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
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Persistent DNA damage-induced NLRP12 improves hematopoietic stem cell function.
Qiqi Lin1,2, Limei Wu1, Zhilin Ma1,2
1Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia, USA.
JCI Insight
|May 22, 2020
Summary
Persistent DNA damage upregulates NOD-like receptor 12 (NLRP12), enhancing hematopoietic stem cell (HSC) function in DNA repair deficiencies and aging. Targeting NLRP12 may offer therapeutic benefits for these conditions.
Area of Science:
- Immunology
- Stem Cell Biology
- Genetics
Background:
- NOD-like receptor 12 (NLRP12) is crucial for innate immunity.
- Previous studies linked DNA damage to NLRP12 upregulation in hematopoietic stem cells (HSCs) lacking Fanca.
- The specific role of NLRP12 in HSC maintenance remained unknown.
Purpose of the Study:
- To investigate the role of NLRP12 in HSC maintenance under conditions of persistent DNA damage, specifically in DNA repair deficiency and aging.
- To determine if NLRP12 upregulation improves HSC function in mouse and human models.
Main Methods:
- Utilized Fanca-/- mice treated with DNA cross-linker mitomycin C or ionizing radiation to induce DNA damage.
- Assessed NLRP12 expression in phenotypic HSCs.
- Performed NLRP12 knockdown and overexpression experiments in HSCs from Fanca-/- mice, aged mice, and human patients.
- Evaluated HSC function, including repopulation capacity, self-renewal, and hematopoietic recovery.
Main Results:
- Persistent DNA damage, induced by mitomycin C or irradiation, upregulated NLRP12 in Fanca-/- HSCs.
- NLRP12 knockdown worsened the HSC repopulation defect in Fanca-/- mice.
- NLRP12 was also upregulated in HSCs from aged mice, and its depletion impaired their function.
- Overexpression of NLRP12 improved the long-term repopulating function of deficient and aged HSCs.
- NLRP12 maintained HSC function in models of Fanconi anemia and human aging.
Conclusions:
- Persistent DNA damage-induced NLRP12 plays a vital role in maintaining HSC function.
- NLRP12 is a potential therapeutic target for DNA repair disorders and age-related decline in HSC function.
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