A Novel Perspective on Stem Cells, Tissue Senescence and Aging: Pluripotent Very Small Embryonic-Like Stem Cells (VSELs) and Hematopoietic Stem Cells (HSCs) Are Prematurely Depleted in Adult Bone Marrow (BM) in Response to Prolonged Growth Hormone/Insulin-Like Growth Factor-1 Signaling (IIS) and Chronic Increase in Caloric Uptake
Authors: Kucia Magda , Ratajczak Janina , Shin Dong-Myung , Liu Rui , Masternak Michal , Bartke Andrzej , Ratajczak Mariusz Z 
Published: October 2019

Abstract
Abstract 4818

Background.
Caloric uptake elevates the plasma level of growth hormone (GH), which subsequently stimulates release of insulin-like growth factor-1 (IGF-1) from the liver. Evidence is accumulating that an increase in caloric intake, which leads to prolonged growth hormone (GH) and insulin/insulin-like growth factors signaling (IIS), accelerates aging. On the other hand, caloric restriction and a resulting decrease in IIS has the opposite effect and extends lifespan (Nature 2010;464:504). In support of this finding, mice with low circulating IGF-1 levels (Laron, Ames, and Snell dwarfs) live much longer than their normal littermates and, conversely, mice with high levels of circulating IGF-1 (e.g., transgenic mice that overexpress bovine growth hormone [bGH]) have significantly reduced life span.

Aim of Hypothesis.
To explain these phenomena, we hypothesized that prolonged IIS prematurely depletes adult tissues of very small embryonic-like stem cells (VSELs), which are the most developmentally primitive adult tissue-residing pluripotent stem cells (Leukemia 2006;20:857). We envision that VSELs play an important role in rejuvenation of the pool of tissue-committed stem cells and, as we observed previously, the number of these cells in murine BM decreases with age. We demonstrated that in bone marrow (BM), VSELs give rise to long-term repopulating hematopoietic stem cells (LT-HSCs) (Leukemia 2011; doi:10.1038/leu.2011.73, Exp. Hematology 2011;39:225–237). As previously reported, VSELs are kept quiescent in BM and protected from premature depletion by erasure of the somatic imprint in differentially methylated regions (DMRs) of some paternally imprinted genes involved in IIS (e.g., Igf2-H19 and RasGRF1).

Results.
In the current study, we provide direct evidence that the number of VSELs deposited in BM during ontogenesis is related to plasma IIS signaling, which is affected by the GH/IGF-1 level. In particular, mice with elevated IGF-I level in plasma due to expression of the bovine GH transgene and wild type mice injected for a sustained period with porcine GH both exhibit significant decreases in the number of VSELs and HSCs in BM compared to control animals. These decreases were paralleled by epigenetic changes in Igf2-H19 and RasGRF1 loci in which DMRs became hypermethylated over time. These changes in methylation lead to increases in IGF-2 and RasGRF1 expression and may explain why bovine GH transgenic mice have an increase in IIS and a significantly reduced life span. Conversely, mice with low circulating plasma IGF-1 levels (Laron and Ames dwarf mice ) have higher numbers of VSELs and HSCs in BM that, in contrast to aged-matched normal littermates, are maintained at high levels even into advanced age. The molecular signature of VSELs in these animals revealed prolonged retention of hypomethylation in the DMRs within the Igf2-H19 and RasGRF1 loci, which attenuated IIS signaling in these cells. The number of VSELs, however, decreased in these animals after prolonged treatment with porcine GH or human recombinant IGF-I.

Conclusions.
Our data shed new light on the relationships between senescence, high GH level, prolonged IIS, and depletion of VSELs and LT-HSCs. Accordingly, we propose a new paradigm in which chronic IIS (e.g., due to chronic high caloric intake and the resulting elevated GH and IGF-1 levels) prematurely depletes VSELs in BM, which leads to a decrease in the number of LT-HSCs. By contrast, caloric restriction and a decrease in IIS may delay the age-dependent elimination of VSELs from BM. This study also indicates that GH-based anti-aging therapies need careful re-evaluation of their potentially uncontrolled stimulation of VSELs in BM and downstream effects on hematopoiesis and the development of hematological malignancies. In support of this concern, elevated IIS may lead to hematological malignancies (uncontrolled proliferation of VSELs), while, by contrast, it is known that Laron dwarf mice and Laron dwarf patients, which have a GH-receptor deficiency and low plasma IGF-1 levels, do not develop leukemias.

Disclosures:
Ratajczak: Neostem Inc: Consultancy, Research Funding.