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Blunting Half of the Double-Edged Sword
Potential Use of Interleukin-10 to Protect Bone Marrow–Derived Cells
After Myocardial Infarction
Matthew L. Springer, Xiaoyin Wang
D
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endothelial cells,15 but, at least in the case of human circulating cells, are presumed by many investigators to retain
their hematopoietic nature and home to angiogenic endothelium, facilitating the proliferation of the resident endothelial
cells.16 Regardless of their derivation or identity, they are
generally presumed to provide a natural healing mechanism,
as they are attracted to multiple signals from ischemic tissue
and improve vascularity.
Krishnamurthy et al14 hypothesized that interleukin-10
(IL-10), which generally exerts a limiting effect on the
inflammatory response, might play a role in the survival and
function of EPCs that have been naturally mobilized, or
therapeutically administered, to the infarcted myocardium.
On surgical induction of MI in a mouse model, EPCs were
mobilized to the circulation, but in an IL-10 knockout (KO)
mouse, EPC mobilization was markedly diminished and
much fewer EPCs were detected in the blood. One of the
basic questions that the authors asked was whether the lack of
IL-10 had an impact on the source or the destination of the
EPC mobilization; that is, was mobilization impaired because
of a defect in the act of EPCs leaving the bone marrow, or a
defect in the target infarcted heart’s ability to send the proper
signals to mobilize the EPCs? Surprisingly, both appear to
play a role. On the one hand, the mobilization of EPCs was
restored in IL-10 KO mice that had their hematopoietic
systems reconstituted with wild-type bone marrow through
bone marrow transplantation, suggesting that the defect in
mobilization was intrinsic to the EPCs in the bone marrow,
or perhaps was due to problems in neighboring hematopoietic cells in the bone marrow niche or other hematopoietic cells playing auxiliary roles. EPCs from IL-10 KO
mice exhibited increased apoptosis and reduced CXCR4
expression in response to inflammatory stimuli and were
impaired in their chemotaxis toward the CXCR4 ligand,
SDF-1. On the other hand, the infarcted heart in the KO
mouse was not upregulating the SDF-1 that was supposed
to mobilize and attract the cells. Systemic administration
of SDF-1 overcame the defect.
So, was the defect in the signal or in the response to the
signal? Additional insight comes from observations in
post– bone marrow transplantation mice that the natural
response to MI resulted in better cardiac function in IL-10
KO mice having wild-type bone marrow than in wild-type
mice having IL-10 KO bone marrow. Most of the evidence
presented appears to implicate the EPCs themselves as
mediators of the IL-10 KO defect, but the direct effect of
IL-10 deficiency on SDF-1 expression in the infarcted
heart suggests a more complex relationship that is not
entirely clear.
uring a myocardial infarction (MI), tissue damage resulting from the ischemia and subsequent reperfusion
injury triggers a complex combination of cellular responses,1
much of which is bone marrow– derived. Some of these
responses involve a harmful inflammatory reaction to cytokines released by dying cardiomyocytes that can exacerbate
the ongoing local structural damage. Other responses are
beneficial, for example, the prohealing arm of the inflammatory response that replaces the necrotic and inflamed region
with a fibrous scar. Still other beneficial effects are thought to
be mediated by mobilized bone marrow cells (BMCs) of
multiple lineages that aid in tissue healing.2,3 Much effort has
gone into harnessing this endogenous cellular response by
harvesting resident or mobilized bone marrow– derived cells
and administering them to post-MI hearts,4 –7 with the hope
that the cells will regenerate myocardium via differentiation2,8 or will preserve at-risk myocardium by actively9 or
passively10 releasing paracrine growth factors or secreting
exosomes.11,12 However, the aforementioned inflammatory
response can cause problems by creating an environment in
the post-MI heart that may be inhospitable for naturally
attracted and therapeutically administered BMCs alike. Moreover, the MI-induced inflammatory response transitions the
BMCs themselves to a more proinflammatory state, interfering with their therapeutic abilities.13
In this issue of Circulation Research, Krishnamurthy and
colleagues14 explore naturally occurring mechanisms of
dampening the inflammatory response that could potentially
augment the efficacy of cell therapy for MI. Their focus is on
a particular subpopulation of BMCs, the endothelial progenitor cells (EPCs). These cells, which were originally discovered in rodents, subsequently have been more thoroughly
characterized in human blood, where they are known not only
as EPCs but also as circulating angiogenic cells among other
identities (see cautionary note below; we will refer to them
here as EPCs for consistency). These bone marrow– derived
circulating cells were initially proposed to differentiate into
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Division of Cardiology (M.L.S.), Cardiovascular Research
Institute (M.L.S., X.W.), and Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research (M.L.S.), University of
California, San Francisco, San Francisco, CA.
Correspondence to Matthew L. Springer, PhD, Division of Cardiology,
Box 0124, University of California, San Francisco, San Francisco, CA
94143-0124. E-mail [email protected]
(Circ Res. 2011;109:1196-1198.)
© 2011 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.111.257352
1196
Springer and Wang
Non-standard Abbreviations and Acronyms
BMCs
EPCs
IL
KO
MI
bone marrow cells
endothelial progenitor cells
interleukin
knockout
myocardial infarction
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Interestingly, systemic administration of IL-10 increased
the number of EPCs detected in and near capillaries, and the
number of capillaries was increased, which is consistent with
the proangiogenic role of EPCs. In culture, treatment of EPCs
with IL-10 increased VEGF transcription, suggesting that
IL-10 may play roles both in blunting the inflammatory
response to preserve EPCs and in stimulating the EPCs to
express angiogenic factors.
One cautionary note is that, to paraphrase an old joke, if
you ask five “EPC” researchers what kind of cells they study,
you’ll get six answers. The term EPC is used freely in the
literature to refer to monocytic cells isolated from the blood
that exhibit endothelial properties, produce angiogenic factors, and do not differentiate into endothelial cells; cells from
blood that differentiate into endothelial cells or perhaps
always were endothelial cells; cells from the bone marrow
that express a variety of specific markers; cells from cord
blood; cells in the embryo, and so forth. Various groups over
the years have used the term to describe their cell population
of interest even if that population had little in common with
the cells originally described by Asahara et al.15 Species
differences are important here as well, because the cells
described in the mouse bone marrow and human blood
express different markers and may not be exactly the same
thing. Thus, it is important to keep in mind that drawing
inferences from the “EPC” literature can involve observations
based on multiple and diverse cell types. Describing the
properties of EPCs can be like discussing the life of “Alfred”
without being clear on whether that is the fellow responsible
for the Nobel Prize, the man who was the master of suspense
films, or Batman’s butler. That said, the EPCs described by
Krishnamurthy et al are clearly therapeutic bone marrow–
derived cells whose function and survival depends, in part, on
IL-10.
When labeled EPCs were transplanted into the infarcted
myocardium, the concurrent systemic administration of IL-10
increased the survival and retention of the EPCs in the
myocardium and decreased proinflammatory cytokines and
infiltration of monocytes/macrophages. While it is tempting
to ponder a possible shift in balance between proinflammatory monocytes/macrophages and prohealing monocytic
EPCs, the authors offer a simpler explanation that the
inflammatory response is detrimental to the survival of EPCs.
This reasoning would be in keeping with the concept that the
post-MI heart is an inflammatory milieu that is inhospitable
to otherwise therapeutic cells and lends credence to the goal
of modulating that milieu to limit inflammation. However,
anti-inflammatory treatment has demonstrable consequences
IL-10 Protects Endothelial Progenitor Cells
1197
for the post-MI heart: by interfering with the healing arm of
the inflammatory response, patients have suffered from weakening of the myocardial wall and ventricular aneurysms.17,18
This bidirectional nature of the inflammatory response is a
classic double-edged sword, and approaches to blunt the
harmful edge without impairing the healing edge will be
important for limiting post-MI myocardial damage as well as
preserving the naturally reparative functions of diverse bone
marrow– derived cells. Thus, more focused inflammatory
modulation remains a worthwhile goal, and the current
Krishnamurthy et al study presents another reason that IL-10
has therapeutic potential in the case of MI.
Sources of Funding
M.L.S. is supported in part by R01 HL086917 and R21 HL097129
from the NIH/NHLBI, R21 DA031966 from the NIH/NIDA, and
Innovative Research Grant 11IRG5250021 from the American Heart
Association.
Disclosures
None.
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KEY WORDS: myocardial infarction 䡲 inflammation
progenitor cells 䡲 bone marrow cells
䡲
IL-10
䡲
endothelial
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Blunting Half of the Double-Edged Sword: Potential Use of Interleukin−10 to Protect Bone
Marrow-Derived Cells After Myocardial Infarction
Matthew L. Springer and Xiaoyin Wang
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 2011;109:1196-1198
doi: 10.1161/CIRCRESAHA.111.257352
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