Insulin-like growth factor-II: a novel autocrine growth factor modulating the apoptosis and maturation of umbilical cord blood erythroid progenitors.
OBJECTIVE
To search a novel function of erythroid progenitor cells circulating as the major nucleated cell population in umbilical cord blood (CB) cells.


METHODS
Human CB-derived CD36(+) erythroid progenitors were subjected to cDNA microarray. Gene expression and biological property of CB-erythroid progenitors and adult peripheral blood (PB)-erythroid progenitors were compared by using real-time polymerase chain reaction (PCR) and serum-free culture system with erythropoietin (EPO).


RESULTS
The microarray revealed 124-fold higher levels of insulin-like growth factor-II (IGF-II) gene expression in CB-CD36(+) erythroid progenitors than in stimulated lymphocytes of adult PB. Real-time PCR verified that IGF-II mRNA levels were highest in CB-CD36(+) erythroid progenitors compared to other CB- or adult PB-fractionated cells. When CB-CD36(+) erythroid progenitors were cultured with EPO in serum-free medium, anti-IGF-II-antibody (Ab) reduced the number of erythroid colonies. When CB- and adult PB-derived erythroid colony-forming cells (ECFCs) were cultured with interleukin-3, stem cell factor, and EPO, mRNA levels per cells of IGF-II peaked on day 12, but those of type 1 and type 2 receptors did not increase with ECFCs maturation. The maturation rate by IGF-II was higher in CB-ECFCs than in adult PB-ECFCs. The majority of CB-ECFCs expressed IGF-II protein. Anti-IGF-II-Ab, but not anti-IGF-I-Ab, reduced the number of CB-ECFCs in liquid culture with EPO. Anti-IGF-II-Ab accelerated apoptosis of ECFCs, assessed by dimethylthiazole tetrazolium bromide, bromodeoxyuridine, and flow cytometric analyses. ECFCs failed to attain full maturity in the presence of anti-IGF-II-Ab.


CONCLUSIONS
These results suggest that IGF-II is produced by erythroid progenitors themselves, and has a crucial role in fetal erythropoiesis by modulating apoptosis and maturation in an autocrine fashion.
Nagatomo
Taro
T
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Muta
Koichiro
K
Ohga
Shouichi
S
Ochiai
Masayuki
M
Ohshima
Koichi
K
Hara
Toshiro
T
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood; D020869:Gene Expression Profiling; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D007335:Insulin-Like Growth Factor II