Effects of organ-specific loss of insulin-like growth factor-I production on murine hematopoiesis1 1The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Abstract

To determine whether circulating insulin-like growth factor (IGF)-I has a role in hematopoiesis, we examined hematologic parameters in mice with markedly reduced serum levels resulting from a liver-specific inactivation of the IGF-I gene. These mice have normal postnatal growth and development, suggesting that local production of IGF-I can maintain anabolic effects. Liver-specific IGF-I-deficient (LID) mice were compared with control littermates with regard to hematopoietic parameters. Spleen cellularity was decreased in the LID mice compared with control mice. Spleen myeloid progenitors, as determined by colony-forming units-granulocyte/monocyte (CFU-GM) and colony-forming units-high proliferative potential (CFU-HPP), were significantly decreased in the LID mice. Immune parameters, as indicated by the absolute number of B and T cells, did not significantly differ between the knockout and control mice. In contrast to the decreased cellularity and myelopoiesis in the spleen, bone marrow cellularity was not different between the 2 groups, but the total femoral content of CFU-GM and CFU-HPP was significantly increased in the LID mice. The decrease in splenic myelopoiesis was not due to the inability of progenitors to exit the bone marrow, because CFU-GM and burst-forming units-erythroid were significantly increased in the blood of LID mice compared with normal littermates. Administration of exogenous IGF-I to the LID mice for 4 days partially restored myelopoietic parameters in the spleen. Liver production of IGF-I and, therefore, normal serum levels of this hormone, although not necessary for general organ growth and development, seems necessary for survival or transition of myeloid progenitors into the spleen.

Distinctive Mesenchymal-Parenchymal Cell Pairings Govern B Cell Differentiation in the Bone Marrow

“…Previous studies reported that IGF-1 promotes B cell expansion in vitro ( Taguchi et al., 2006 ) and that activation of the IGF-1 receptor is needed for immunoglobulin production ( Baudler et al., 2005 ). Local IGF-1 production may be most important for marrow B lymphopoiesis, as prior studies of either liver or pituitary-specific IGF-1 deficiency only observed altered B cell numbers in the spleen and not within the bone marrow ( Montecino-Rodriguez et al., 1997 , Welniak et al., 2004 ). Our data indicate that osteoprogenitors secrete IL-7 and IGF-1; both are necessary to support full B lineage differentiation in the bone marrow ( Figure 7 I).…”

Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency

“…IGF-IR silencing in these cells resulted in a decrease in the number of circulating neutrophils [ 19 ]. Moreover, in a mouse model of liver IGF-I deficiency (LID), congenital loss of IGF-I was associated with a decrease in the number of myeloid derived progenitor cells [ 20 ]. Additionally, IGF-IR silencing by a small interfering RNA was shown to induce the production of the pro-inflammatory cytokines TNF-α and INF-γ and consequently, alter host immunity in a mouse model of breast cancer [ 21 ].…”

The Triterpenoid CDDO-Me Promotes Hematopoietic Progenitor Expansion and Myelopoiesis in Mice

“…Single cell suspensions (1 × 10 6 ) were prepared from the spleen and bone marrow as described previously (14) and labeled with fluorochrome-conjugated anti-mouse antibodies, and nonspecific binding was corrected with isotype-matched controls. FITC anti-CD11b (M1/70), PE-Cy5 anti-Gr-1 (RB6-8C5), PE-Sca-1 (D7), FITC c-kit (2B8) and 7-AAD were purchased from BD Biosciences.…”

“…CFU-GM, BFU-e and CFU-HPP colony assays were performed as previously described (14, 15). For CFU-GM and BFU-e assays, 5 × 10 4 bone marrow cells or 5 × 10 5 splenocytes were plated in 35mm Petri dishes with methylcellulose-containing medium.…”