Resident macrophages influence stem cell activity in the mammary gland.
BACKGROUND
Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. Although it is well established that macrophages influence normal mammopoiesis, the mammary cell types that these accessory cells influence have not been determined. Here we have explored a role for macrophages in regulating mammary stem cell (MaSC) activity, by assessing the ability of MaSCs to reconstitute a mammary gland in a macrophage-depleted fat pad.


METHODS
Two different in vivo models were used to deplete macrophages from the mouse mammary fat pad, allowing us to examine the effect of macrophage deficiency on the mammary repopulating activity of MaSCs. Both the Csf1op/op mice and clodronate liposome-mediated ablation models entailed transplantation studies using the MaSC-enriched population.


RESULTS
We show that mammary repopulating ability is severely compromised when the wild-type MaSC-enriched subpopulation is transplanted into Csf1op/op fat pads. In reciprocal experiments, the MaSC-enriched subpopulation from Csf1op/op glands had reduced regenerative capacity in a wild-type environment. Utilizing an alternative strategy for selective depletion of macrophages from the mammary gland, we demonstrate that co-implantation of the MaSC-enriched subpopulation with clodronate-liposomes leads to a marked decrease in repopulating frequency and outgrowth potential.


CONCLUSIONS
Our data reveal a key role for mammary gland macrophages in supporting stem/progenitor cell function and suggest that MaSCs require macrophage-derived factors to be fully functional. Macrophages may therefore constitute part of the mammary stem cell niche.
Gyorki
David E
DE
VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic 3052, Australia. gyorki@wehi.edu.au
Asselin-Labat
Marie-Liesse
ML
van Rooijen
Nico
N
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
D000273:Adipose Tissue; D000818:Animals; D002478:Cells, Cultured / Q000166:cytology; D004002:Clodronic Acid / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D008081:Liposomes / Q000008:administration & dosage; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014185:Transplantation, Isogeneic
D008081:Liposomes; D004002:Clodronic Acid; D016173:Macrophage Colony-Stimulating Factor
Breast Cancer Res. 2002;4(4):155-64
12100741
Nature. 2006 Feb 23;439(7079):993-7
16395311
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):99-104
15615857
J Mammary Gland Biol Neoplasia. 2006 Oct;11(3-4):229-38
17115264
Development. 2000 Jun;127(11):2269-82
10804170
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9312-6
7937762
J Immunol Methods. 1994 Sep 14;174(1-2):83-93
8083541
Trends Cell Biol. 2004 Nov;14(11):628-38
15519852
Nature. 2006 Jan 5;439(7072):84-8
16397499
Dev Biol. 2002 Jul 1;247(1):11-25
12074549
J Biomed Biotechnol. 2001;1(3):133-143
12488607
Blood. 2002 Jan 1;99(1):111-20
11756160