Age-dependent effects of Igf2bp2 on gene regulation, function, and aging of hematopoietic stem cells in mice

Abstract

Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPC) during aging. The Lin28b/Hmga2 pathway controls tissue development and the postnatal downregulation of this pathway limits the self-renewal of adult vs. fetal hematopoietic stem cells (HSC). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates mRNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. Here, we show in an analysis of wildtype and Igf2bp2 knockout mice that Igf2bp2 regulates oxidative metabolism in HSPC and the expression of metabolism, protein synthesis, and stemness-related genes in HSC of young mice. Interestingly, Igf2bp2 expression and function strongly decline in HSC aging. In young mice, Igf2bp2-deletion mimics aging-related changes of HSC, including changes in Igf2bp2-target gene expression and the impairment in colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status has no effect on these parameters in HSC. Unexpectedly, Igf2bp2 deficient mice exhibit an amelioration of the aging-associated increase of HSC numbers and myeloid skewed differentiation. Together, Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSC, which is required for full HSC function at young adult age. However, Igf2bp2 gene function is lost during aging and it appears to contribute to HSC aging in two ways: (i) the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSC and (ii) the activity of Igf2bp2 at young age contributes to aging-associated HSC expansion and myeloid skewing.

IGF2BP2, an RNA‐binding protein regulates cell proliferation and osteogenic differentiation by stabilizing SRF mRNA

“…IGF2BP2 is therefore important in regulating both nonterminal and terminal differentiation. In vivo, in IGF2BP2‐knockout mice, IGF2BP2‐knockdown significantly inhibited stem cell proliferative ability and promoted stem cell differentiation (Suo et al, 2022), consistent with our conclusions. Other studies have also addressed the effects of IGF2BP2 deletion on stem cell proliferation and differentiation (Dai et al, 2015; Regué et al, 2019).…”

“…IGF2BP2 is therefore important in regulating both nonterminal and terminal differentiation. In vivo, in IGF2BP2-knockout mice, IGF2BP2-knockdown significantly inhibited stem cell proliferative ability and promoted stem cell differentiation (Suo et al, 2022), consistent with our conclusions.…”

Schlafen2 is a regulator of quiescence in adult murine hematopoietic stem cells

“…We also found down-regulation of Igf2bp2 , which has recently been shown to be important for the function of young HSC in mice. 21 Additionally Ccnb2 along with the also upregulated gene Ifi27l1 have previously been found upregulated in HSC of IFN-treated mice. 22 We also found upregulation of Cd53 , which is involved in IL2 signaling and thus also connected to inflammation and IFN.…”

Ageing as a software design flaw

“…More recent studies using high throughput approaches have also revealed links between changes during development and ageing [10,40,49,100,101], as highlighted in epigenetic clocks [21,22,42]. Other recent studies, for example of hematopoietic stem cells in mice [102] and the aryl hydrocarbon receptor [103], further support the concept that developmental pathways influence ageing phenotypes later in life. Although these studies are encouraging, many open questions remain.…”