Unexpected Evidence That Chronic IGF-1 Deficiency In Laron Dwarf Mice Maintains High Levels of Hematopoietic Stem Cells (HSCs) In BM - Are HSCs Gradually Depleted From BM with Age In An IGF-1–dependent Manner? Implications for the Novel Effect of Caloric Restriction on the Hematopoietic Stem Cell Compartment and Longevity.

Abstract 1551

Insulin-like growth factor-1 (Igf-1) or somatomedin is an important factor affecting proliferation of several types of cells, but its role in hematopoiesis remains controversial. Secretion of Igf-1 in the liver is stimulated directly by the growth hormone (GH)–GH receptor (GH-R) axis and indirectly by a high calorie diet. We have previously reported that Igf-1 does not directly stimulate proliferation of hematopoietic progenitors (J Clin Invest. 1994;94:320). However, our recent data indicate that Igf-1 stimulates proliferation of so-called very small embryonic-like stem cells (VSELs), that as we demonstrated, are the most developmentally primitive stem cells in adult bone marrow (BM) (Leukemia 2006;20:857) and may give rise to long-term repopulating hematopoietic stem cells (LT-HSCs) (Leukemia 2010; in press doi:10.1038/leu.2010.121). We envision that VSELs play a role in rejuvenation of the pool of tissue-committed stem cells in some tissues (e.g., HSCs and MSCs in BM) and we observed that the number of these cells in murine BM decreases with age. We also observed that erasure of the somatic imprint on some paternally imprinted genes (e.g., Igf2-H19 and RasGRF1) results in attenuation of insulin/insulin-like factors (e.g., Ins/Igf-1 signaling), keeps VSELs quiescent in BM, and protects them from uncontrolled proliferation. In the current work, to shed more light on the role of Igf-1 on hematopoiesis and stem cell compartment, we analyzed BM isolated from murine Laron dwarfs, which due to a genetic mutation in the GH-R, maintain very low levels of Igf-1 in peripheral blood (PB) and interestingly are long-living animals (Nature 2010;464:504). Analysis of PB cell counts, however, did not reveal any differences in the number of erythrocytes, platelets, and leucocytes between Laron dwarf mice and wild type controls. In striking contrast, however, we observed that Laron dwarf mice have in BM i) a ∼4–5-fold increase in the number of Sca-1⁺c-kit⁺lineage^- (SKL) cells and ii) a >4-fold higher number of clonogenic CFU-Mix, CFU-GM, BFU-E, and CFU-Meg cells. Interestingly, Laron dwarfs also maintained ∼3-fold higher number of VSELs in BM tissue. Since the Igf-1 level is regulated by calorie uptake, these data shed new light on caloric restriction, senescence, and the hematopoietic stem cell compartment. Accordingly, we propose a new paradigm in which chronic Igf-1 deficiency somehow protects VSELs from age-related elimination from BM. This mimics a situation seen in chronic caloric restriction where the Igf-1 level is low and this results in longevity. Since the long-living Laron dwarf mice that maintain low levels of Igf-1 have higher numbers of VSELs and HSCs in BM, we postulate that chronically elevated levels of Igf-1, resulting e.g., from high calorie uptake, may lead to premature depletion of the stem cell pool, including VSELs and HSCs, and thus be responsible for premature aging. This hypothesis is currently being tested in animals that overexpress Igf-1, and interestingly, in contrast to IGF-1–deficient Laron dwarf mice, appear to have much shorter lifespans. Further studies are needed that will link the effect of chronic high Igf-1 signaling with the development of hematological malignancies. Of note, murine Laron dwarfs are significantly protected from developing cancer and human Laron dwarfs with chronic low Igf-1 level do not develop malignancies at all.