Paternal Insulin-like Growth Factor 2 (Igf2) Regulates Stem Cell Activity During Adulthood

Insulin-like Growth Factor 2 (IGF2) belongs to the IGF/Insulin pathway, a highly conserved evolutionarily network that regulates growth, aging and lifespan. Igf2 is highly expressed in the embryo and in cancer cells. During mouse development, Igf2 is expressed in all sites where hematopoietic stem cells (HSC) successively expand, then its expression drops at weaning and becomes undetectable when adult HSC have reached their niches in bones and start to self-renew. In the present study, we aim to discover the role of IGF2 during adulthood. We show that Igf2 is specifically expressed in adult HSC and we analyze HSC from adult mice deficient in Igf2 transcripts. We demonstrate that Igf2 deficiency avoids the age-related attrition of the HSC pool and that Igf2 is necessary for tissue homeostasis and regeneration. Our study reveals that the expression level of Igf2 is critical to maintain the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSC and their niche. Our data have major clinical interest for transplantation: understanding the changes in adult stem cells and their environments will improve the efficacy of regenerative medicine and impact health- and life-span. Paternal Igf2 regulates stem cells frequency and activity lifelong following a spatio-temporal gradient of expression. Upper panel: Igf2 high and broad expression during pre-natal life drops after weaning then becomes restricted to tissue stem cells. Lowering paternal Igf2 has no obvious effect on life span. However, lowering Igf2 levels delays the end of post-natal growth and the onset of adulthood. Lower panel: Igf2 deficiency avoids the age-related decrease of the stem cells pool by reducing stem cells activity and differentiation. Therefore, Igf2 function would be to regulate stem cells by maintaining their capacity to support hematopoiesis and to interact with their environment, which is coherent with the presence of Igf2 in the IGF/Insulin longevity pathway. The activity of stem cells during development, homeostasis and regeneration, would follow an innate mechanism involving Igf2. Igf2 level would give stem cells a temporal identity and act as a timing regulator of their activity life long. [Display omitted] •The imprinted gene Igf2 is expressed in adult tissue stem cells.•Igf2 deficiency increases HSC (hematopoietic stem cells) self-renewal and avoids age-related attrition of the HSC pool.•Igf2 deficiency decreases HSC different