Ferlosio, A

Orlandi, A

FERLOSIO, AMEDEO

ORLANDI, AUGUSTO

English

Diabetes and aging: a different phenotypic commitment of circulating and resident stem cells?

Amedeo Ferlosio

Augusto Orlandi

Crossref

Acta Diabetologica

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Archivio della Ricerca - Università di Roma Tor vergata

1 23
Acta Diabetologica
 
ISSN 0940-5429
 
Acta Diabetol
DOI 10.1007/s00592-012-0432-z
Diabetes and aging: a different phenotypic
commitment of circulating and resident
stem cells?
Amedeo Ferlosio & Augusto Orlandi
1 23
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LETTER TO THE EDITOR
Diabetes and aging: a different phenotypic commitment
of circulating and resident stem cells?
Amedeo Ferlosio • Augusto Orlandi
Received: 12 September 2012 / Accepted: 13 September 2012
 Springer-Verlag Italia 2012
Atherosclerosis is a vascular disease largely attributed to
chronic vascular injury, and its clinical manifestations
appear more frequently in aged subjects. Accumulation of
vascular smooth muscle cells in the tunica intima plays a
major role in the pathogenesis of atherosclerosis. Arterial
smooth muscle cells are heterogeneous even in the normal
vessel wall and display more marked different phenotypes
in pathological conditions. Smooth muscle cells in ath-
erosclerotic plaques display a de-differentiated or ‘‘syn-
thetic’’ phenotype compared to a ‘‘contractile’’ phenotype
in the normal media. Aorta stiffens with age and other
cardiovascular risk factors. In particular, diabetes-induced
activation of the renin–angiotensin system increases the
expression of angiotensin II, further increasing aortic cal-
cification and stiffness. Thus, alterations of aortic and
carotid walls in patients with diabetes were traditionally
considered a sort of ‘‘accelerated aging.’’ In the last years,
the contribution of stem cells to atherosclerosis has been
highlighted. Bone marrow and peripheral blood-derived
endothelial and vascular smooth muscle cell resident pro-
genitors both contribute to vascular remodeling during
atherogenetic process and aging [1]. Both circulating and
resident progenitor cells have been evocated to contribute
to the response of the adult arterial wall to damage.
Chronic treatment with bone marrow-derived progenitor
cells from young non-atherosclerotic ApoE-/- mice pre-
vents atherosclerosis progression in ApoE-/- recipients
despite persistent hypercholesterolemia, whereas bone
marrow-derived progenitor cells from older ApoE-/- mice
with atherosclerosis were much less effective [2]. These
findings suggest that the progressive bone marrow-derived
progenitor cells deficit may contribute to the development
of atherosclerosis. Nevertheless, atherosclerotic lesions are
characterized from the increase of stem cell marker-
expressing cells, and macroscopically normal aortas from
human and rat aged donors show an increased number of
VEGFR-1? and c-kit? cells in the thickened intima [3].
Also, diabetes alters the function of circulating progenitor
cells. Depletion of bone marrow-derived angiogenic cell
populations may further promote atherogenesis and aortic
calcification in patients with diabetes mellitus [4]. In
multivariable analyses, the increase in colony-forming
units from endothelial progenitor cells was associated with
the decrease in coronary artery and abdominal aortic cal-
cification [5]. These changes were not associated with
changes in CD34? expression, suggesting that a decreased
angiogenic potential contributes to the development of
human atherosclerosis. Moreover, decreasing colony-
forming capacity associated with the progressive increase
of calcification scores [5]. Recently, it has been reported
that diabetes mellitus patients had significantly higher
expression of osteocalcin and bone alkaline phosphatase on
circulating VEGFR-2?/CD34? progenitor cells than con-
trol subjects [6]. Moreover, cultured VEGFR-2?/CD34?
cells from diabetes mellitus patients formed structures
highly suggestive of calcified nodules, strongly suggesting
that circulating progenitor cells from diabetic patients show
a drift toward a pro-calcific phenotype that may be driven
by inflammatory signals in response to injury [6], similarly
to that observed in non-vascular tissues [7]. Monocyte–
macrophage recruitment is a crucial step for a correct
angiogenesis, and this mechanism is mainly mediated by
VEGFR-1, that favors the increase of vessel lumen, vessel
Communicated by Massimo Federici.
A. Ferlosio  A. Orlandi (&)
Department of Biomedicine and Prevention, University of Rome,
‘‘Tor Vergata’’ Via Montpellier 1, 00133 Rome, Italy
e-mail: orlandi@uniroma2.it
123
Acta Diabetol
DOI 10.1007/s00592-012-0432-z
Author's personal copy
stabilization and monocyte–macrophage infiltration and
counteracts pathological angiogenesis stimulated from
PlGF-mutated variants that not bind VEGFR-1 [8, 9].
These findings suggest that aging and diabetes share the
decrease of circulating endothelial cells with potential
angiogenic/reparative properties, but in addition, diabetes
associates a conversion toward a pro-calcific phenotype,
whereas with aging stem cells with a synthetic VEGFR-1?
myocitic phenotype prevail and contribute to aortic myo-
intimal thickening and to vascular angiogenetic or healing
processes [10, 11]. Although these findings support the
divergent phenotypic conversion of circulating precursor
cells, further studies are needed to verify whether also
aortic resident stem cells are similarly modified in their
differentiative capacities in diabetic patients.
References
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muscle cells in vascular disease. Biochem Pharmacol 79:1706–
1713
2. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T,
Gregg D, Ramaswami P et al (2003) Aging, progenitor cell
exhaustion, and atherosclerosis. Circulation 108:457–463
3. Ferlosio A, Arcuri G, Doldo E, Scioli MG, De Falco S, Spagnoli
LG et al (2012) Age-related increase of stem marker expression
influences vascular smooth muscle cell properties. Atheroscle-
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(2010) The relationship between coronary artery calcification
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Diabetes and aging: a different phenotypic commitment of circulating and resident stem cells?

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