We propose that paternal Igf levels

We propose that paternal Igf2 levels regulate the intrinsic requirement of stem l-name manufacturer from the zygote stage. Widespread Igf2 expression during embryonic development would contribute to the rapid and harmonious development of organs, then its restriction to adult stem cells would control body homeostasis lifelong, by regulating temporal changes in stem cells (see Graphical Abstract). The maintenance of broad Igf2 expression in adult humans but not in adult mice must reflect their different needs in cell proliferation and regeneration, related to different sizes and life spans. Our study adds imprinting and heterochrony as new dimensions to the IGF/Insulin pathway, and reveals that the evolutionary conservation of Igf2 parental imprinting might play a key role in longevity by protecting tissues. Altogether, these data suggest that Igf2 might act throughout life as regulator of a stem cells intrinsic program, coherent with the protective role of the IGF/Insulin pathway toward the organism. In conclusion, we have uncovered a role for Igf2 that is linked to health-span rather than to lifespan. We show that lowering Igf2 levels is a promising way to enhance the HSC pool, while avoiding the uncontrolled proliferation and migration of immature cells that would lead to transformation events often associated with aging (Sun et al., 2014). Our study helps to understand changes occurring in stem cells and their environment during aging and tissue regeneration (Voog and Jones, 2010). This has major clinical interest for transplantation in elderly people: understanding the changes in aging stem cells and their environments will improve the efficacy of regenerative medicine and extend health- and life-span. The following are the supplementary data related to this article.
Conflict of Interest
Author Contributions
Acknowledgments We are grateful for the support of the staff of the iRCM animal facility during the mouse studies, of the iRCM and Imeti cytometry facilities for cell sorting experiments and of the iRCM irradiation platform. We thank Dr. Iscove, Dr. Jurdic, Dr. Goodhardt, Dr. Vainchenker, Dr. Dusanter-Fourt, Dr. Marcand and Dr. Karess for helpful comments. We thank Dr. Romeo and Dr. Nagy for support and discussion. This work was supported by INSERM (Institut National de la Santé et de la Recherche Médicale) and by CEA (Commissariat à l\'Energie Atomique).
Introduction Type 1 diabetes mellitus is characterized by progressive loss of pancreatic β-cells, leading to a life-long dependence on exogenous insulin. In addition, β-cells are reportedly decreased in patients with type 2 diabetes (Butler et al., 2003). In this context, regeneration of pancreatic β-cells is a promising therapeutic strategy for not only type 1 but also some forms of type 2 diabetes. We (Hasegawa et al., 2007) and other groups (Hess et al., 2003, Nakayama et al., 2009) previously reported bone marrow (BM) transplantation (BMT) to promote pancreatic β-cell proliferation after pharmacological β-cell injury, such as that caused by streptozotocin (STZ) treatment. Bone marrow-derived cells were found to have infiltrated sites around regenerating islets (Hess et al., 2003, Hasegawa et al., 2007), suggesting a secretory factor(s) from bone marrow cells to be involved in the underlying mechanism. However, despite intensive research, the specific secretory protein(s)/peptide(s) involved in pancreatic β-cell regeneration after BMT has not as yet been identified. In addition to secretory proteins, microRNAs (miRNAs) which are transported in exosomes have recently attracted considerable attention for their roles in inter-cellular communication. Exosomes are lipid nano-vesicles, and are secreted by many types of cells and contain a variety of molecules including miRNAs (Turchinovich et al., 2013, Hirsch et al., 2013). miRNAs are a class of endogenous, small, non-coding RNAs that negatively regulate gene expression via translational inhibition or degradation of their target mRNAs (Bartel, 2009). miRNAs have been shown to regulate basic cellular functions including cell proliferation, differentiation, and death (Shenoy and Blelloch, 2014). Therefore, we hypothesized that miRNAs transferred into exosomes mediate the mechanism underlying β-cell regeneration in response to BMT, and comprehensively examined miRNA levels in serum exosomes in BMT-mice. We found that two microRNAs, miR-106b-5p and miR-222-3p, contribute to BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation, thereby ameliorating hyperglycemia of insulin-deficient diabetes.