Key Points

  • Genetic deletion of Gdf11 does not affect red blood cell formation during homeostasis or after transplant.

  • Hematopoietic stem cell function is preserved in mice lacking Gdf11 expression within the blood lineage.

Abstract

Tightly regulated production of mature blood cells is essential for health and survival in vertebrates and dependent on discrete populations of blood-forming (hematopoietic) stem and progenitor cells. Prior studies suggested that inhibition of growth differentiation factor 11 (GDF11) through soluble activin receptor type II (ActRII) ligand traps or neutralizing antibodies promotes erythroid precursor cell maturation and red blood cell formation in contexts of homeostasis and anemia. As Gdf11 is expressed by mature hematopoietic cells, and erythroid precursor cell expression of Gdf11 has been implicated in regulating erythropoiesis, we hypothesized that genetic disruption of Gdf11 in blood cells might perturb normal hematopoiesis or recovery from hematopoietic insult. Contrary to these predictions, we found that deletion of Gdf11 in the hematopoietic lineage in mice does not alter erythropoiesis or erythroid precursor cell frequency under normal conditions or during hematopoietic recovery after irradiation and transplantation. In addition, although hematopoietic cell-derived Gdf11 may contribute to the pool of circulating GDF11 protein during adult homeostasis, loss of Gdf11 specifically in the blood system does not impair hematopoietic stem cell function or induce overt pathological consequences. Taken together, these results reveal that hematopoietic cell–derived Gdf11 is largely dispensable for native and transplant-induced blood formation.

REFERENCES

REFERENCES
1.
Dussiot
M
,
Maciel
TT
,
Fricot
A
, et al
.
An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia
.
Nat Med
.
2014
;
20
(
4
):
398
-
407
.
2.
Suragani
RN
,
Cadena
SM
,
Cawley
SM
, et al
.
Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis
.
Nat Med
.
2014
;
20
(
4
):
408
-
414
.
3.
Loffredo
FS
,
Steinhauser
ML
,
Jay
SM
, et al
.
Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy
.
Cell
.
2013
;
153
(
4
):
828
-
839
.
4.
Sinha
M
,
Jang
YC
,
Oh
J
, et al
.
Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle
.
Science
.
2014
;
344
(
6184
):
649
-
652
.
5.
Garbern
J
,
Kristl
AC
,
Bassaneze
V
, et al
.
Analysis of Cre-mediated genetic deletion of Gdf11 in cardiomyocytes of young mice
.
Am J Physiol Heart Circ Physiol
.
2019
;
317
(
1
):
H201
-
H212
.
6.
McPherron
AC
,
Lawler
AM
,
Lee
SJ
.
Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11
.
Nat Genet
.
1999
;
22
(
3
):
260
-
264
.
7.
de Boer
J
,
Williams
A
,
Skavdis
G
, et al
.
Transgenic mice with hematopoietic and lymphoid specific expression of Cre
.
Eur J Immunol
.
2003
;
33
(
2
):
314
-
325
.
8.
McPherron
AC
,
Huynh
TV
,
Lee
SJ
.
Redundancy of myostatin and growth/differentiation factor 11 function
.
BMC Dev Biol
.
2009
;
9
(
1
):
24
.
9.
Madisen
L
,
Zwingman
TA
,
Sunkin
SM
, et al
.
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
.
Nat Neurosci
.
2010
;
13
(
1
):
133
-
140
.
10.
Ogilvy
S
,
Metcalf
D
,
Gibson
L
,
Bath
ML
,
Harris
AW
,
Adams
JM
.
Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment
.
Blood
.
1999
;
94
(
6
):
1855
-
1863
.
11.
El-Brolosy
MA
,
Kontarakis
Z
,
Rossi
A
, et al
.
Genetic compensation triggered by mutant mRNA degradation
.
Nature
.
2019
;
568
(
7751
):
193
-
197
.
12.
Ma
Z
,
Zhu
P
,
Shi
H
, et al
.
PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components
.
Nature
.
2019
;
568
(
7751
):
259
-
263
.
13.
Guerra
A
,
Oikonomidou
PR
,
Sinha
S
, et al
.
Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia
.
Blood
.
2019
;
134
(
6
):
568
-
572
.
14.
Smith
SC
,
Zhang
X
,
Zhang
X
, et al
.
GDF11 does not rescue aging-related pathological hypertrophy
.
Circ Res
.
2015
;
117
(
11
):
926
-
932
.
15.
Harper
SC
,
Johnson
J
,
Borghetti
G
, et al
.
GDF11 decreases pressure overload-induced hypertrophy, but can cause severe cachexia and premature death
.
Circ Res
.
2018
;
123
(
11
):
1220
-
1231
.
16.
Poggioli
T
,
Vujic
A
,
Yang
P
, et al
.
Circulating growth differentiation factor 11/8 levels decline with age [published correction appears in
Circ Res
.
2018
;
122
(
1
):
e3
-
e4
]
.
Circ Res
.
2016
;
118
(
1
):
29
-
37
.
17.
Egerman
MA
,
Cadena
SM
,
Gilbert
JA
, et al
.
GDF11 increases with age and inhibits skeletal muscle regeneration
.
Cell Metab
.
2015
;
22
(
1
):
164
-
174
.
18.
Hammers
DW
,
Merscham-Banda
M
,
Hsiao
JY
,
Engst
S
,
Hartman
JJ
,
Sweeney
HL
.
Supraphysiological levels of GDF11 induce striated muscle atrophy
.
EMBO Mol Med
.
2017
;
9
(
4
):
531
-
544
.
19.
Jones
JE
,
Cadena
SM
,
Gong
C
, et al
.
Supraphysiologic administration of GDF11 induces cachexia in part by upregulating GDF15 [published correction appears in Cell Rep. 2018;22(12):3375]
.
Cell Rep
.
2018
;
22
(
6
):
1522
-
1530
.
20.
Pop
R
,
Shearstone
JR
,
Shen
Q
, et al
.
A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression
.
PLoS Biol
.
2010
;
8
(
9
):
e1000484
.
You do not currently have access to this content.