During EPO or anemia challenge, erythroid progenitor cells transit through a selectively expandable proerythroblast pool.
Investigations of bone marrow (BM) erythroblast development are important for clinical concerns but are hindered by progenitor cell and tissue availability. We therefore sought to more specifically define dynamics, and key regulators, of the formation of developing BM erythroid cell cohorts. A unique Kit(-)CD71(high)Ter119(-) "stage E2" proerythroblast pool first is described, which (unlike its Kit(+) "stage E1" progenitors, or maturing Ter119(+) "stage E3" progeny) proved to selectively expand ∼ 7-fold on erythropoietin challenge. During short-term BM transplantation, stage E2 proerythroblasts additionally proved to be a predominantly expanded progenitor pool within spleen. This E1→E2→E3 erythroid series reproducibly formed ex vivo, enabling further characterizations. Expansion, in part, involved E1 cell hyperproliferation together with rapid E2 conversion plus E2 stage restricted BCL2 expression. Possible erythropoietin/erythropoietin receptor proerythroblast stage specific events were further investigated in mice expressing minimal erythropoietin receptor alleles. For a hypomorphic erythropoietin receptor-HM allele, major defects in erythroblast development occurred selectively at stage E2. In addition, stage E2 cells proved to interact productively with primary BM stromal cells in ways that enhanced both survival and late-stage development. Overall, findings reveal a novel transitional proerythroblast compartment that deploys unique expansion devices.
Dev
Arvind
A
COBRE Center of Excellence in Stem Cell Biology and Regenerative Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.
Fang
Jing
J
Sathyanarayana
Pradeep
P
Pradeep
Anamika
A
Emerson
Christine
C
Wojchowski
Don M
DM
D000483:Alleles; D000740:Anemia; D000818:Animals; D016026:Bone Marrow Transplantation; D002450:Cell Communication / Q000502:physiology; D049109:Cell Proliferation; D004900:Erythroblasts / Q000166:cytology*; D015672:Erythroid Precursor Cells / Q000166:cytology*; D004920:Erythropoiesis; D004921:Erythropoietin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017467:Receptors, Erythropoietin / Q000235:genetics; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells
D017467:Receptors, Erythropoietin; D004921:Erythropoietin
Biochem Biophys Res Commun. 2002 May 10;293(3):1124-31
12051776
Nat Med. 2006 Jul;12(7):793-800
16799557
J Cell Biol. 2007 Jun 4;177(5):871-80
17548514
FEBS Lett. 2009 Jun 18;583(12):1873-9
19427863
Blood. 2009 Apr 16;113(16):3845-56
19064729
J Immunol. 2009 Feb 15;182(4):1781-7
19201828
Blood. 2007 Jul 15;110(2):509-18
17403918
Nat Biotechnol. 2005 Jan;23(1):69-74
15619619
J Biol Chem. 2008 May 2;283(18):11897-904
18285334
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):773-7
7846049
Blood. 2006 Sep 15;108(6):2064-71
16690966
Mol Cell Biol. 2005 Aug;25(15):6355-62
16024775
Curr Top Dev Biol. 2008;82:23-53
18282516
Nat Immunol. 2004 Sep;5(9):919-26
15311278
Mol Cell Biol. 2007 Jun;27(12):4261-72
17420275
Stem Cells. 2007 Apr;25(4):1062-9
17420230
Cell. 1995 Mar 10;80(5):729-38
7889566
Nat Immunol. 2009 Oct;10(10):1110-7
19734904
Cell. 1999 Jul 23;98(2):181-91
10428030
Cell. 1995 Oct 6;83(1):59-67
7553874
Blood. 2007 Oct 1;110(7):2361-70
17548578
J Biol Chem. 1995 Mar 10;270(10):5631-5
7534299
Blood. 2009 Jan 22;113(4):911-8
18927434
J Biol Chem. 2006 Jul 21;281(29):20181-9
16707498
Blood. 2008 Jun 1;111(11):5390-9
18349318
J Immunol. 2008 Jul 1;181(1):383-92
18566404
Nature. 2005 Sep 29;437(7059):754-8
16193055
Mol Cell. 2008 May 23;30(4):415-25
18498746
Dev Cell. 2009 Oct;17(4):527-40
19853566
Exp Hematol. 2009 Feb;37(2):151-8
19100675
Curr Opin Hematol. 2008 May;15(3):155-61
18391778
Science. 2006 Jun 23;312(5781):1763-6
16794074
Blood. 1994 Nov 15;84(10):3494-504
7949103
Blood. 2008 Aug 1;112(3):470-8
18650462
Nat Med. 2004 Jan;10(1):64-71
14702636
J Exp Med. 2003 May 5;197(9):1205-11
12732662
Development. 2000 Nov;127(22):4949-58
11044408
Nat Rev Immunol. 2009 Jul;9(7):480-90
19543225
EMBO J. 2001 Jun 15;20(12):3156-66
11406592
Blood. 2005 Apr 1;105(7):2741-8
15591122
Cell. 1996 Sep 20;86(6):897-906
8808625
Curr Opin Hematol. 2006 May;13(3):137-41
16567955
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13087-92
18755895
Blood. 2005 Jun 15;105(12):4604-12
15705783
J Biol Chem. 1994 Jan 7;269(1):614-20
8276859
Blood Cells Mol Dis. 2008 Sep-Oct;41(2):141-7
18501646
Crit Rev Oncol Hematol. 2005 Apr;54(1):63-75
15780908
Mol Cell Biol. 1996 Apr;16(4):1622-31
8657137
Blood. 1998 Oct 15;92(8):2940-50
9763581
J Exp Med. 1995 Jan 1;181(1):411-5
7528776
J Clin Invest. 2008 Feb;118(2):583-96
18188450
J Exp Med. 2005 Apr 18;201(8):1197-203
15837809
J Clin Invest. 2006 Mar;116(3):683-94
16511603
Rev Hematol. 1958 Jan-Mar;13(1):8-11
13555228