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Reviews
Adv Clin Exp Med 2012, 21, 2, 249–254
ISSN 1899–5276
© Copyright by Wroclaw Medical University
Ewelina Drela, Katarzyna Stankowska, Arleta Kulwas, Danuta Rość
Endothelial Progenitor Cells in Diabetic Foot Syndrome
Śródbłonkowe komórki progenitorowe w zespole stopy cukrzycowej
Department of Pathophysiology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Poland
Abstract
In the late 20th century endothelial progenitor cells (EPCs) were discovered and identified as cells capable of differentiating into endothelial cells. Antigens characteristic of endothelial cells and hematopoietic cells are located on
their surface. EPCs can proliferate, adhere, migrate and have the specific ability to form vascular structure, and they
have a wide range of roles: They participate in maintaining hemostasis, and play an important part in the processes
of vasculogenesis and angiogenesis. They are sources of angiogenic factors, especially vascular endothelial growth
factor (VEGF). EPCs exist in bone marrow, from which they are recruited into circulation in response to specific
stimuli. Tissue ischemia is thought to be the strongest inductor of EPC mobilization. Local ischemia accompanies
many pathological states, including diabetic foot syndrome (DFS). Impaired angiogenesis – in which EPCs participate – is typical of DFS. An analysis of the available literature indicates that in diabetic patients the number of EPCs
declines and their functioning is impaired. Endothelial progenitor cells are crucial to vasculogenesis and angiogenesis during ischemic neovascularization. The pathomechanisms underlying impaired angiogenesis in patients with
DFS is complicated, but the discovery of EPCs has shed new light on the pathogenesis of many diseases, including
diabetes foot syndrome (Adv Clin Exp Med 2012, 21, 2, 249–254).
Key words: endothelial progenitor cells, diabetic foot syndrome.
Streszczenie
Śródbłonkowe komórki progenitorowe (EPCs – endothelial progenitor cells) zostały odkryte jako komórki wykazujące zdolność do różnicowania w komórki śródbłonka. Na swej powierzchni mają antygeny charakterystyczne
zarówno dla komórek śródbłonka, jak i komórek hematopoetycznych. EPCs wykazują cechy proliferacji, adhezji,
migracji oraz posiadają swoistą zdolność tworzenia struktur naczyniowych. Wachlarz ról pełnionych przez EPCs
jest szeroki: biorą udział w utrzymaniu hemostazy, odgrywają istotną rolę w procesach waskulogenezy i angiogenezy. Są źródłem czynników angiogennych, zwłaszcza naczyniowo śródbłonkowego czynnika wzrostu (VEGF
– vascular endothelial growth factor). EPCs egzystują w szpiku kostnym, skąd są rekrutowane do krążenia pod
wpływem określonych bodźców. Za najsilniejszy czynnik mobilizujący EPCs do krwi krążącej jest uważane niedotlenienie tkanek. Miejscowa hipoksja towarzyszy wielu patologicznym stanom, w tym zespołowi stopy cukrzycowej
(DFS – diabetic foot syndrome). DFS charakteryzuje się nieprawidłową angiogenezą, w której biorą udział EPCs.
Z analizy dostępnej literatury wynika, iż liczba EPCs u pacjentów z cukrzycą jest zmniejszona oraz obserwuje się
upośledzenie ich funkcji. Śródbłonkowe komórki progenitorowe są kluczowym elementem w budowaniu naczyń
krwionośnych podczas neowaskularyzacji indukowanej niedotlenieniem. Patomechanizm leżący u podłoża nieprawidłowej angiogenezy u pacjentów z DFS jest skomplikowany, a odkrycie EPCs rzuciło nowe światło na patogenezę
wielu schorzeń, w tym zespołu stopy cukrzycowej (Adv Clin Exp Med 2012, 21, 2, 249–254).
Słowa kluczowe: śródbłonkowe komórki progenitorowe, zespół stopy cukrzycowej.
The existence of endothelial progenitor cells
(EPCs) was suggested in the second half of the
20th century. Pearson noted that in 1963 Stump
et al. published the results of a study in which
they observed that dacron grafts implanted in
a pig thoracic aorta were completely covered by
a monolayer of non-thrombogenic cells that were
histologically similar to cells of the endothelium
[1]. Pearson also pointed out that the origin of endothelial cells was described by Risau and Flamme
in the 1990s, when they postulated that endothelial cells and hematopoietic cells derived from the
same mesenchymal precursor: the hemangioblast,
and described the differentiation of precursor cells
into endothelial cells taking place during embryonic vasculogenesis [1].
250
As Pearson notes, a study conducted by Takayuki Asahara et al. in 1997 was a milestone in the
discovery of EPCs: The authors isolated monocytic
cells from human blood which, in appropriate culture conditions, showed the expression of markers
characteristic of endothelial cells (CD31+, E-selectin+, eNOS+ and uptake of modified low-density
lipoprotein [LDL]) [1]. Up until then, the widelyheld view was that the differentiation of mesenchymal cells occurs exclusively during embryonic
development, but the findings reported by Asahara
et al. demonstrated the existence of hematopoietic
progenitor cells in adults. Urbich and Dimmeler
noted that in 1998, Shi et al. described circulating
endothelial progenitor cells (CEPCs) in adults [2].
EPCs and CEPCs have specific antigens for hematopoietic stem cells and for endothelial cells [2].
The discovery of endothelial progenitor cells has
shed a new light on the pathogenesis of many diseases, including diabetes mellitus, and has opened
a new avenue in their treatment.
Endothelial Progenitor Cells
EPCs are cells with the ability to differentiate
into endothelium cells. They demonstrate the expression of markers characteristic of hematopoietic cells (CD34+, CD133+) and endothelial cells
(KDR, vWF, CD31+, VE-cadherin, eNOS+, uptake
of acetylated LDL and binding lectins such as Ulex
europaeus) [3–5]. EPCs are a heterogenic group of
cells that show the expression of various surface
antigens. Immature endothelial cells have a marker peculiar to stem cells: CD133 (also known as
AC133). During the differentiation process this antigen gradually disappears; mature endothelial cells
do not have CD133, but still show the expression of
CD34, another stem cell marker [4, 6]. EPCs present in peripheral blood can be at different stages
of endothelial differentiation, so researchers distinguish different subpopulations of EPCs. Silvestre
demonstrated the presence of early and late EPCs
derived from cultured human peripheral blood
mononuclear cells [5]. Early EPCs express antigens
characteristic of the monocytic lineage. The peak
growth of this population of EPCs occurs during
the 2nd and 3rd weeks of cultivation; they do not survive beyond the 4th week. Late EPCs, which demonstrate the expression of VE-cadherin, Flt-, KDR
and CD45, appear between the 2nd and 3rd weeks of
cultivation with expotential growth from the 4th to
8th weeks, and live for an average of 12 weeks [5].
It is known that circulating CD34+ cells have
vasculogenic properties and are able to differentiate
into cells with endothelial characteristics [4]. However, cells characterized as EPCs may derive from
E. Drela et al.
the CD14+myeloid/monocyte lineage [5]. Pearson
wrote that in 2003 Rehman et al. conducted a study
in which they observed that cells forming early EPC
colonies were characterized by a weak expression
of the CD34 antigen, but showed strong expression of CD45 (a panleukocyte marker) and CD14
(a monocyte marker); they also found that these
cells were barely able to proliferate [1]. Rehman et
al. suggested that these cells were not progenitors
of the endothelium, but that they could participate
in the angiogenesis process in vivo due to their secretion of angiogenic mediators such as vascular
endothelial growth factor (VEGF) and granulocyte
colony-stimulating factor (G-CSF) [1].
In Urbich and Dimmeler’s opinion the same
controversies concern the origin of EPCs isolated
from mononuclear cells from human peripheral blood [2]. They wrote: “In peripheral blood
mononuclear cells, several possible sources for
endothelial cells may exist: (1) the rare number of
hematopoietic stem cells, (2) myeloid cells, which
may differentiate to endothelial cells under the
cultivation selection pressure, (3) other circulating
progenitor cells (eg, “side population” cells), and
(4) circulating mature endothelial cells, which are
shed off the vessel wall” [2]. Circulating blood is
not only the source of EPCs. As Ranjan et al. pointed out [7], various researchers have isolated EPCs
from umbilical cord blood [8], bone marrow [9],
adipose tissue [10], skeletal muscles [11] and from
such organs as the heart [12] and spleen [13].
EPCs exist in the bone marrow, from which
they are recruited under the influence of specific
stimulating signals and become circulating EPCs
(CEPCs) [3, 14, 15]. In physiological conditions
the number of circulating EPCs is low, but it increases in response to stimuli. Hypoxia is regarded as the strongest inductor for mobilizing EPCs
from the bone marrow into circulation [3, 15, 16].
Hypoxia mobilizes EPCs via the hypoxia-sensing
system, which involves hypoxia-inducible factor 1
(HIF-1). HIF-1 is a transcription factor composed
of alpha and beta subunits. The HIF-1β subunit
is expressed constitutively, but expression of the
HIF-1α subunit is regulated by the concentration
of oxygen [3]. At the correct oxygen concentration,
the HIF-1α subunit is quickly degraded by ubiquitin proteolysis. The ischemia state slows down
the degradation of the alpha subunit, which can
dimerize with the beta subunit. The active HIF1 factor binds to the correct region of the DNA
and activates the transcription of genes, including
the vascular endothelial growth factor gene SDF1α and the erythropoietin gene [3]. The kinase
insert domain receptor (KDR) is a receptor for
VEGF located on the surface of bone marrow stem
cells. The transduction of a signal by a EGF-KDR
251
EPCs in Diabetic Foot Syndrome
complex activates endothelial nitric oxide synthase
(eNOS). Next, nitric oxide activates matrix metalloproteinase 9 (MMP-9), which releases the stem
cell-active cytokine, soluble Kit ligand. This cytokine causes hematopoietic stem cells to leave their
quiescent niche and pass to a proliferation niche,
and stimulates them to enter circulation [15, 16].
Growth factors (mainly VEGF) regulate EPC
migration, but chemokin SDF-1α plays a role in
EPC homing to ischemic tissue [1, 2, 15]. Fadini
et al (2007) put forward the hypothesis that an
inability to mobilize EPCS from bone marrow is
connected with the downregulation of HIF-1α and
a reduced concentration of factors like VEGF and
SDF-1α [3].
Endothelial progenitor cells can proliferate, adhere, migrate and have the specific ability to form
vascular structures [3]. Their proliferation is manifested as the ability to expand and form colonies
in culture, and it is induced by local ischemia or
growth factors. Angiogenesis or reendothelialization require another property of EPCs: adhesion
[3], which is possible because of the presence of an
adhesion molecule and selectin on the surface of the
cells (β2-integrins or L-selectin) [5]. Integrins play
an important role in mediating cell-to-cell interactions. They enable various cells, including hematopoietic cells, to adhere to the extracellular matrix
(ECM) and endothelial cells. β2-integrins and α4β1integrins are responsible for cell-to-cell interaction.
β1-integrins are located on the surface of various
cell types, including endothelial cells; β2-integrins
are preferentially expressed by hematopoietic cells.
β2-integrins can also be found on peripheral bloodderived EPCs and are needed for EPC adhesion to
endothelial cells and transendothelial migration in
vitro [2]. Thus, the presence of adhesion molecules
is required for ischemic tissue to arrest EPCs. After adhesion, endothelial progenitor cells migrate
through the ECM. The highest form of specialization for functional EPCs is the ability to form
vascular tubes. This property is necessary for the
creation of new vascular vessels [2, 5, 14].
Endothelial progenitor cells take part in hemostasis, constituting a circulating pool of cells with
the ability to “patch” injuries to the endothelial layer
by replacing cells which have succumbed to apoptosis or been lost in other circumstances [3, 17].
EPCs play an important role in vasculogenesis and
angiogenesis. Vasculogenesis, which dominates in
the embryonic period, causes vessels to be created
de novo. It was previously thought that post-natal
creation of blood vessels occurs via angiogenesis,
through the migration and proliferation of mature
endothelial cells, but the isolation of EPCs from peripheral blood indicates that these cells participate
in vasculogenesis in adults [4, 18].
EPCs in Diabetic Foot
Syndrome
Bone-marrow-derived endothelial progenitor cells are the crucial elements in post-ischemic
neovascularization [19]. Hypoxia is a pathological
state that occurs in various diseases, especially in
diabetes. Among the consequences of long-lasting
unregulated type 2 diabetes mellitus (T2DM) are
angiopathic complications: microangiopathy and
macroangiopathy. Coexisting neuropathy and impaired wound healing contribute to the development of diabetic foot syndrome (DFS). DFS is the
most frequent cause of amputation: According to
the International Diabetes Federation (IDF), worldwide, every 30 seconds an amputation of a lower
limb is performed because of diabetes [20].
The pathogenic model underlying abnormal
angiogenesis in diabetic patients is complicated.
The isolation of EPCs has contributed to understanding the processes involved. Studies conducted by independent groups of scientists show
that abnormal EPC functioning and impaired
EPC mobilization from the bone marrow in diabetic patients is caused by hyperglycemia [21]. The
number of circulating EPCs is small under normal
circumstances, but is elevated in response to hypoxia or injury [18]. Reduced numbers of EPCs
and impairment of their functioning are observed
in patients with diabetes and in animals with induced diabetes [17, 21].
A study conducted by Loomans et al. shows
the influence of hyperglycemia on EPCs [17]. The
study involved mice in which hyperglycemia had
been induced by intraperitoneal injections of streptozotocin (80 mg/kg body weight) and a control
group of healthy mice. The authors noted a 40% reduction in the number of EPCs and a 50% increase
in the number of macrophages in the mice with
hyperglycemia as compared to the control group.
In the authors’ opinion, the reduction in the number of EPCs and their impaired functioning were
the result of the toxic influence of hyperglycemia
on myeloid bone marrow progenitors [17].
Similar findings were reported by Fadini et al.
(2005), who showed that a high glucose concentration could initiate the process of apoptosis in
cultured endothelial cells [21]. A common complication of diabetes mellitus is peripheral vascular
disease (PVD). The group examined by Fadini et
al. was made up of 51 patients: 24 diabetic patients
with PVD, 16 diabetics without PVD and 11 nondiabetics with PVD. The control group consisted of
17 healthy volunteers. The researchers reported a decreased number of EPCs and circulating progenitor cells (CPCs) in diabetic patients as compared to
252
the healthy volunteers, stating that in patients with
T2DM the number of EPCs in peripheral blood is
reduced by about 40%. What is more, comparing
only the subgroups with PVD, a reduced number of
CPCs was noted in the patients with diabetes; and
a decreased number of EPCs and CPCs was noted
in diabetic patients with ischemic foot as compared
to the control group and to diabetic patient with
PVD but without ischemic foot [21].
The influence of hyperglycemia on circulating
progenitor cells was also studied by Krankel et al.,
who observed that a high concentration of glucose
was a crucial factor in inducing apoptosis and reducing the proliferation of CPCs. They also found
that hyperglycemia reduced MMP-9 activity [22].
The decreased number of EPCs in diabetic
patients is connected with impaired recruitment
of these cells from the bone marrow. A study conducted by Gallagher et al. on an animal model demonstrated that reduced EPC mobilization is a result
of impaired eNOS phosphorylation in the bone
marrow [15]. The authors found a 50% reduction
in circulating EPCs in diabetic mice as compared
to mice without induced diabetes. They also observed decreased SDF-1α expression on myofibroblasts and endothelial cells isolated from diabetic
peripheral cutaneous wounds [15]. Caballero et al.
also noted reduced EPC mobilization from bone
marrow and decreased EPC numbers in circulation
in patients with diabetes [23]. CD34 cells isolated
from diabetic patients demonstrated abnormal migration in response to SDF-1α EPCs isolated from
diabetic individuals show disorders of proliferation,
adhesion and deformability compared with nondiabetic EPCs. Caballero et al. hypothesized that EPC
homing to wounds may be impaired by the influence of advanced end glycation products (AGEs)
[23]. AGEs modify blood vessel walls, especially
the basement membranes, through cross-linking;
the altered vessel wall makes it difficult to recruit
EPCs to the angiogenesis site and hindering their
participation in the whole repair process [23].
Yan et al. suggested that abnormal EPC functioning results from coexisting oxidative stress
[19]. Their results show that EPC concentration in
peripheral blood was higher in the control group
than in mice with type 1 or type 2 diabetes. Increased EPC migration induced via VEGF was
observed in the control group as compared to the
diabetic groups [19].
Some authors have observed an inverse correlation between glycated hemoglobin and the
number of endothelial progenitor cells [17, 18,
24]. Churdchomjan et al. published their study
“Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic control compare EPC function in type 2 dia-
E. Drela et al.
betes with good and poor glycemic control” [14],
in which they observed that the number of EPCs
was higher in patients with good glycemic control
than in patients with poor control. They suggested
that the decreased number of EPCs was caused by
decreased survival of these cells in circulation [14].
This study demonstrates the importance of diabetes management, but it is a problem that requires
further research.
In patients with diabetes, a paradox is observed: Depending on the kind of tissue, different
concentrations of the same cytokines (VEGFs)
and EPCs are found. Retinopathy shows increased
VEGF level and EPCs in the retina, while diabetic
patients with peripheral arterial disease demonstrate a decreased number of EPCs [25]. In diabetic foot syndrome, which is a late diabetes complication, local decreased VEGF synthesis and EPC
reduction is observed. These changes contribute
to abnormal angiogenic response. Impaired angiogenesis leads to tissue ischemia. A consequence
of the long-lasting ischemia is the development of
non-healing wounds and in severe cases necrosis,
for which an amputation is the only effective therapy. Impairment of the blood vessel regeneration
process seems to be an important reason for the
amputation of lower limbs in patients with DFS.
More and more attention is being paid to the
genetic mechanism underlying impaired endothelial progenitor cell recruitment from bone marrow
in patients with DFS. An example is the study investigating the relationship between the SDF-1 genotype and neovascularization in diabetes foot syndrome [26]. Humpert et al. noticed that in patients
with DFS and accompanying macrovascular disease, heterozygous SDF-1 3. A genotype appeared
more often [26]. This chemokine is responsible for
EPC homing. On the other hand, it induces platelet aggregation and is expressed on atherosclerotic
plaques [26]. It may be hypothesized that excessive
expression of the specific SDF-1 genotype may increase the risk of macroangiopathy, thus limiting
the role of homing cytokine.
The authors concluded that the role of endothelial progenitor cells in post-natal neovasculariazation is indisputable. This process is very important for patients with diabetic foot syndrome.
Abnormal biological activity and a decline in the
mobilization of EPCs from bone marrow are results of the toxic influences of hyperglycemia. The
decreased secretion of proangiogenic factors and
reduced number of EPCs – elements that are crucial to the formation of blood vessels formation –
contribute to an abnormal process of angiogenesis.
Exploring the connection between EPCs, VEGF
and DFS appears to be a worthwhile avenue for
further research.
EPCs in Diabetic Foot Syndrome
253
References
[1] Pearson JD: Endothelial progenitor cells - hype or hope? J Thromb Haemost 2009, 7, 255–262.
[2] Urbich C, Dimmeler S: Endothelial progenitor cells: characterization and roles in vascular biology. Circ Res 2004,
95, 343–353.
[3] Fadini GP, Sartore S, Agostini C, Avogaro A: Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care 2007, 5, 1305–1312.
[4] Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N: CD34-/CD133 +VEGFR- 2 + Endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res 2006, 98, e20-e25.
[5] Silvestre JS: Vascular progenitor cells and diabetes: roles in postischemnic neovascularization. Diab Metabol 2008
34, 533–536.
[6] Ding H, Triggle Ch: R. Endothelial cell dysfunction and the vascular complications associated with type 2 diabetes:
assessing the health of the endothelium. Vasc Health Risk Manag 2005, 1, 55–71.
[7] Ranjan AK, Kumar U, Hardikar AA, Poddar P, Nair PD, Hardikar AA: Human blood vessel-derived endothelial
progenitors for endothelialization of small diameter vascular prosthesis. PLoS One 2009, 4 (11), e7718.
[8] Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Equchi H, Onitsuka I, Matsui K, Imaizumi T: Transplanted
cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 2000, 105,
1527–1536.
[9] Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishiola A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MA,
Storb RF, Hammond WP: Evidence for circulating bone marrow-derived endothelial cells. Blood 1998, 92, 362–367.
[10] Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat M, Clerque M, Manneville C, SaillaBarreau C, Duriez M, Tedqui A, Levy B, Penicaud L, Casteilla L: Plasticity of human adipose lineage cells toward
endothelial cells: physiological and therapeutic perspectives. Circulation 2004, 109, 656–663.
[11] Majka SM, Jackson KA, Kienstra KA, Majesky MW, Goodell MA, Goodell MA, Hirschi KK: Distinct progenitor
populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J Clin Invest 2003, 111, 71–79.
[12] Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K,
Leri A, Kajstura I, Nadal-Ginard B, Anversa P: Adult cardiac stem cells are multipotent and support myocardial
regeneration. Cell 2003, 114, 763–776.
[13] Werner N, Junk S, Laufs U, Link A, Walenta K, Bohm M, Nickenig G: Intravenous transfusion of endothelial
progenitor cells reduces neointima formation after vascular injury. Circ Res 2003, 93, e17–24.
[14] Churdchomjan W, Kheloamai P, Manochantr S, Tapanadechopone ChP, Tantrawatpan CH, U-pratya Y,
Issaragrisil S: Comparison of endothelial progenitor cell function in type 2 diabetes with good and poor glycemic
control. BMC Endocr Dis 2010, 10, 5.
[15] Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC: Diabetic
impairments in NO-mediated endothelail progenitor cell mobilization and homing are reversed in order to hyperoxia and SDF-1 α. J Clin Invest 2007, 117, 1249–1259.
[16] Liu ZJ, Velazquez OC: Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing. Antioxid
Redox Signal 2008, 10, 1869–1882.
[17] Loomans C, van Haperen R, Duijs JM, Verseyden C, de Crom R, Leenen P, Drexhage HA, de Boer HC, de
Koning EJP, Rabelink TJ, Staal FJT, van Zonneveld AJ: Differentiation of bone marrow-derived endothelial progenitor cells is shifted into proinflammatory phenotype in order to hyperglycemia. Mol Med 2009, 15, 152–159.
[18] Tepper OM, Galiano RD, Capla JM, Kalka Ch, Gagne PJ, Jacobovitz GR, Levine JP, Gurther GC: Human
endothelial progenitor cells from type 2 diabetics exhibit impaired proliferation, adhesion, and incorporation into
vascular structures. Circulation 2002, 106, 2781–2786.
[19] Yan J, Tie G, Park B, Yang Y, Nowicki PT, Messina LM: Recovery from hindlimb ischemia is less effective in type
2 than in type 1 diabetic mice: roles of eNOS and endothelial progenitor cells. J Vasc Surg 2009, 50, 1412–1422.
[20] Karnafel W: Diabetic foot-pathogenesis and treatment. Lekarz 2009, 11, 26–32.
[21] Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A,
Agostini C, Avogaro A: Circulating endothelial progenitor cells are reduced in peripheral vascular complications
of type 2 diabetes mellitus. J Am Coll Card 2005, 9, 1449–1457.
[22] Krankel N, Adams V, Linke A, Gielen S, Erbs S, Lenk K, Schuler G, Hambrecht R: Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 2005, 25,
698–703.
[23] Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, Kern TS, Grant MB: Ischemic vascular
damage can be repaired by healthy, but not diabetic endothelial progenitor cells. Diabetes 2007, 56, 960–967.
[24] Spinetti G, Kraenkel N, Emanueli C, Madeddu P: Diabetes and vessel wall remodeliling: from mechanistic
insights to regenerative therapies. Cardiovasc Res 2008, 78.
[25] Fadini GP, Sartore S, Baesso I, Lenzi M, Agostini C, Tiengo A, Avogaro A: Endothelial progenitor cells and the
diabetic paradox. Diabetes Care 2006, 3, 714–716.
[26] Humpert PM, Battista MJ, Lammert A, Reismann P, Djuric Z, Rudofsky G Jr, Zorn M, Morcos M, Hammes HP,
Nawroth PP, Bierhaus A: Association of stromal cell-derived factor 1 genotype with diabetic foot syndrome and
macrovascular disease in patients with type 2 diabetes. Clin Chem 2006, 52 (6), 1206–8.
254
E. Drela et al.
Address for correspondence:
Ewelina Drela
Department of Pathophysiology
Collegium Medicum in Bydgoszcz
Skłodowskiej-Curie 9
85-094 Bydgoszcz
Poland
E-mail: [email protected]
Tel.: +48 52 585 35 91
Conflict of interest: None declared
Received: 22.03.2011
Revised: 6.10.2011
Accepted: 29.03.2012