2 DECEMBER 2016 • VOL 354 ISSUE 6316 1103 SCIENCE
between the galaxies in a vast reservoir that
extends across 70 kpc. Stars are condensing
out of this vast reservoir at a rate of at least
hundreds per year (11), which will fall onto
the galaxy to grow its outer layers.
Some of the gas within this reservoir must
be recycled material that was once situated
within stars. This is because Emonts et al. detect the carbon monoxide molecule. Whereas
hydrogen was formed a few minutes after
the Big Bang throughout the universe, the
heavier nuclei of carbon and oxygen are only
formed in vast quantities within the inner
regions of stars. Because the gas reservoir
contains carbon and oxygen molecules, at
least some fraction of it must have once been
inside earlier generations of stars.
The presence of heavy nuclei in the reservoir has important consequences. Gas
expelled from stars is initially very hot and
joins the hot halo in an ionized state. The
cooling rate of gas is much faster when elements heavier than hydrogen are present,
so the recycled gas ensures that cold material for stellar production can more readily
precipitate out of the surrounding hot halo
to form the cold molecular reservoir.
The detection of this vast cloud of recycled molecular gas may help solve the problem of how massive galaxies grow, but it also
throws up new questions. What expels the
recycled gas out of the galaxies? How does
this gas cool down to form molecules? And
how widespread is this mode of galaxy
growth? The Spiderweb galaxy is just one
galaxy in the young universe, and further recycled reservoirs will need to be observed to
determine whether this is a common route
by which massive galaxies grow. j
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“To observe how massive
galaxies accrete cold gas,
Emonts et al. turned their
attention to the Spiderweb
By Pia Sommerkamp1 and
Hematopoietic stem cells (HSCs) are at the helm of the hierarchically or- ganized hematopoietic system that ensures the lifelong production of all blood cells. HSCs depend on meta- bolic cues to secure their protective
quiescent status and to enable rapid activation and replenishment of the blood system
in response to stressful situations such as
infections, excessive bleeding, or chemother-apy-induced myeloablation (1–3). On pages
1156 and 1152 of this issue, Ito et al. (4) and
Taya et al. (5), respectively, uncover important roles for the degradation of defective mitochondria (mitophagy) and the amino acid
valine in HSC maintenance and function.
Phenotypic HSCs isolated by flow cytometry from mouse bone marrow represent a
rather heterogenous cell population (6, 7).
Ito et al. genetically engineered mice to express green fluorescent protein under the
control of regulatory elements that govern
the expression of the Tie2 gene. TIE2 is a
receptor tyrosine kinase that responds to
the growth factor angiopoietin-1, and the
angiopoietin-1–TIE2 pathway is important
for HSC maintenance (8). Remarkably, 68%
of TIE2-expressing (TIE2+) HSCs showed reconstitution capacity after transplantation as
individual cells. These HSCs are located near
arteriolar structures in the bone marrow,
rather than at sinusoids (9). They also exhibit
enhanced cell cycle quiescence, sit atop the
hematopoietic cell hierarchy, and preferentially undergo symmetric stem cell division.
To identify the gene networks that regulate
TIE2+ HSCs, Ito et al. performed single-cell
gene expression analysis combined with ge-
netic deletion studies. They found increased
expression of genes encoding the transcrip-
tion factors promyelocytic leukemia (PML)
and peroxisome proliferator–activated re-
ceptor-delta (PPARd), which regulate fatty
acid oxidation (FAO). This links to earlier
data showing that the PML-PPARd-FAO
axis controls HSC maintenance (10). Ito et
al. further extend this pathway to PPARd-
controlled mitophagy, which is mediated
by the E3 ubiquitin ligase subunit PARKIN
and the PTEN-induced putative protein ki-
nase 1 (PINK1) (4). Mitophagy enables sym-
metric cell division and replenishment of
the hematopoietic system even under stress
conditions. This metabolic cue—minimizing
oxidative stress by increasing mitophagy—is
thus characteristic of highly potent TIE2+
HSCs and is also conserved in human HSCs.
The authors further show that targeting the
PPARd-FAO-mitophagy axis with PPARd ago-
nists enabled the expansion of TIE2+ HSCs
in culture and in mice, suggesting potential
clinical applications (see the figure).
During homeostasis, HSCs are maintained
in a protective dormant state. However, during normal blood production and especially
in response to physiological stress, HSCs
must produce progeny while maintaining
their functional and genomic integrity to
prevent malignant transformation (1). The
findings of Ito et al. suggest that cycling
HSCs can eliminate damaged mitochondria
and thus limit the production of mutagenic
reactive oxygen species. Indeed, limited mitochondrial biogenesis has been cited as crucial
for HSC maintenance (11). Overall, these data
suggest a model in which HSCs can switch
to various metabolic programs depending on
the physiological needs. By targeting these
metabolic cues, cell fate manipulation and
HSC expansion might be feasible.
The metabolic characteristics of HSCs
have recently attracted attention (2), but little is known about the role of single amino
acids for HSC function. Taya et al. show that
bone marrow contains 100-fold higher concentrations of all 20 amino acids compared
to peripheral blood. To test the requirement
of each amino acid for in vitro and in vivo
HSC maintenance, they used single amino
acid–depleted culture media or mouse chow.
These analyses revealed that mouse HSC
proliferation and maintenance depends on
the branched-chain amino acid valine. It
is secreted by vascular endothelial stromal
cells, suggesting that valine may be a critical
component of the HSC niche. Indeed, after 4
Metabolic cues for
hematopoietic stem cells
Manipulating mitophagy and dietary valine
may lead to stem cell therapies
1Division of Stem Cells and Cancer, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg,
Germany. 2Heidelberg Institute for Stem Cell Technology and
Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer
Feld 280, 69120 Heidelberg, Germany. Email: email@example.com