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One of the cardinal features of wound healing is the formation of new small blood vessels at the site

of injury. Salah satu bagian terpenting dalam proses penyembuhan luka adalah pembentukan
pembuluh darah kecil pada lokasi luka. One of the ways in which this happens is by bone marrow-
derived progenitor cells called Endothelial Progenitor Cells (EPCs), in a process known as
vasculogenesis. Salah satu sel yang berperan dalam proses yang disebut vaskulogenesis ini adalah
Endothelial Progenitor Cells (EPC), suatu sel progenitor yang berasal dari sumsum tulang. Poor
healing of diabetic wound is characterized by impaired vasculogenesis. Proses penyembuhan luka
yang buruk ditandai dengan terganggunya proes vaskulogenesis. The process by which EPCs lead to
the formation of new blood vessels involves two important linksthe mobilization of EPCs from
bone marrow into circulation and the recruitment of EPCs from the circulation to the repair site.
Terdapat sebuah proses dimana EPC berperan dalam pembentukan pembuluh darah baru yang
melibatkan dua hal mobilisasi EPC dari sumsum tulang menuju sirkulasi dan perpindahan EPC dari
sirkulasi ke lokasi luka. The cascade begins when a vessel growth-promoting factor called VEGF
(Vasoactive Endothelial Growth Factor) is released by ischemic tissue, like a diabetic wound
complicated by decreased blood flow. Proses ini bermula ketika VEGF (Vasoactive Endothelial Growth
Factor), sebuah faktor yang berperan dalam pembentukan pembuluh darah dilepaskan oleh jaringan
iskemik, seperti luka diabetik yang diperburuk dengan menurunnya aliran darah ke lokasi luka
tersebut. VEGF goes to the bone marrow and activates an enzyme called nitric oxide synthase (NOS)
which, as the name suggests, produces a diffusible chemical called nitric oxide or NO. VEGF akan
menuju sumsum tulang dan mengaktifasi suatu enzim yang bernama nitric oxide synthase (NOS),
dimana seperti dapat terlihat dari namanya, akan menghasilkan substansi kimia yang dapat berdifusi,
yaitu nitric oxide atau NO. This increased NO leads to the mobilization of EPCs from the bone marrow
into the circulation. Peningkatan kadar NO ini akan mengakibatkan perpindahan EPC dari sumsum
tulang menuju sirkulasi. Once in the circulation, they need to migrate to the site of repair. Setelah
berada dalam sirkulasi, mereka akan berpindah ke lokasi luka. This is dependent on the increased
levels of a chemical called SDF-1 which attracts the EPCs to the workplace (see Fig 1). Proses ini
akan terjadi tergantung dari ada atau tidaknya peningkatan substansi kimia yang disebut SDF-1 yang
akan menarik EPC ke daerah lokasi luka. At the wound site, they begin the process of
neovascularization (i.e., formation of new blood vessels) and healing. Pada lokasi luka, mereka akan
memulai proses neovaskularisasi (pembentukan pembuluh darh baru) dan proses penyembuhan
luka. Now what goes wrong with chain of events in diabetes was unknown, that is, until recently.
Sekarang kita dapat menemukan rangkaian proses apa yang terganggu dalam proses penyembuhan
luka pada penderita diabetes.

Figure 1. Mechanisms of wound healing in healthy people versus people with diabetes. Gambar 1.
Mekanisme penyembuhan luka pada orang sehat versus penderita diabetes. In healthy individuals
(left), the acute wound healing process is guided and maintained through integration of multiple
signals released by keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets and other
cells. Pada orang sehat (kiri) proses penyembuhan luka yang akut terjadi akibat adanya integrasi dari
sinyal-sinyal yang dilepaskan oleh keratinosit, fibroblas, sel-sel endotelial, makrofag, dan platelet dan
sel-sel lainnya. During wound-induced hypoxia, VEGF released by macrophages, fibroblasts, and
epithelial cells induces the activation of NOS in the bone marrow, resulting in an increase in NO
levels, which triggers the mobilization of bone marrow EPCs to the circulation. Dalam luka yang
diinduksi oleh hipoksia, Vasoactive Endothelial Growth Factor (VEGF) dilepaskan oleh makrofag,
fibroblas, dan sel-sel epitelial akan mengaktifkan Nitric Oxide Synthase (NOS) dalam sumsum tulang,
sehingga mengakibatkan peningkatan jumlah NO, yang akhirnya akan mengaktifkan mobilisasi
sumsum tulang Endothelial Progenitor Cell (EPC) ke dalam sirkulasi. The chemical SDF-1 promotes
the homing of these EPCs to the site of injury, where they participate in neovasculogenesis. Substansi
kimia SDF-1 menyebabkan kembalinya EPC ke lokasi luka, dimana mereka berperan dalam proses
neovaskulogenesis. Gallagher and colleagues show that in a mouse model of diabetes (right), NOS
activation in the bone marrow is impaired, which directly limits EPC mobilization from the bone
marrow into the circulation. Gallagher dkk menunjukkan bahwa pada tikus percobaan yang
menderita diabetes, aktifasi NOS dalam sumsum tulang terganggu, yang secara langsung akan
membatasi mobilitas EPC dari sumsum tulang ke dalam sirkulasi. They also show that SDF-1
expression is decreased in the diabetic wound, which prevents EPC recruitment to wounds and
therefore limits wound healing. Mereka juga menunjukkan bahwa produksi SDF-1 berkurang pada
luka penderita diabetes, yang membuat jumlah EPC yang terdapat pada lokasi luka juga ikut
berkurang, yang akhirnya akan membatasi proses penyembuhan luka. The authors further show that
establishing hyperoxia in wound tissue (via HBO therapy) activated NOS, increased NO levels, and
enhanced EPC mobilization to the circulation. Penulis lebih jauh lagi mengemukakan bahwa dengan
membuat jaringan luka menjadi hiperoksia (melalui terapi HBO) akan mengaktifkan NOS,
meningkatkan kadar NO, dan meningkatkan mobilisasi EPC ke dalam sirkulasi. However, local
administration of SDF-1 was required to trigger homing of these cells to the wound site. Akan
tetapi, pemberian SDF-1 lokal juga diperlukan untuk menginduksi kembalinya sel-sel ini ke lokasi
luka. These results suggest that HBO therapy combined with SDF-1 administration may be a
potential therapeutic option to accelerate diabetic wound healing alone or in combination with
existing clinical protocols. Jadi dapat disimpulkan bahwa terapi HBO yang dikombinasikan dengan
pemberian SDF-1 dapat menjadi terpi pilihan yang berpotensi untuk meningkatkan proses
penyembuhan luka pada penderita diabetes atau dapat dikombinasikan dengan protokol pengobatan
yang sudah ada.

KESIMPULAN: PERPINDAHAN EPC DARI SUMSUM TULANG MENUJU SIRKULASI DIPENGARUHI OLEH
KADAR NO, SEDANGKAN PERPINDAHAN EPC DARI SIRKULASI MENUJU LOKASI LUKA DIPENGARUHI
OLEH KADAR SDF-1. PADA PENDERITA DIABETES, AKTIFASI NOS DALAM SUMSUM TULANG
TERGANGGU SEHINGGA MENGHAMBAT KEDUA PROSES YANG BERPERAN DALAM
NEOVASKULOGENESIS (PEMBENTUKAN PEMBULUH DARAH BARU) DALAM PROSES PENYEMBUHAN
LUKA.
JYI is supported by: The National Science Foundation, The Burroughs Wellcome Fund, Glaxo
Wellcome Inc., Science Magazine, Science's Next Wave, Swarthmore College, Duke University,
Georgetown University, and many others.

Copyright 1998-2008 The Journal of Young Investigators, Inc.

Diabetic? Sick of those non-healing ulcers? Heres a good news!

Gurjot Singh, Science Journalist

Bachelors in Medicine and Surgery (MBBS), Bangalore Medical College

25 May 2007 - Impaired wound healing is a major clinical problem in diabetic patients, affecting
about 15 percent of them and is the leading cause of lower limb amputations. Reporting in the May
issue of The Journal of Clinical Investigation, researchers at the University of Pennsylvania Medical
Center have, for the first time, identified the molecular basis of impaired vasculogenesis in diabetic
wound healing. By fixing the defective links in the process, they were able to significantly enhance
wound healing, thus providing novel potential targets for therapeutic intervention in diabetic wound
healing. The current therapies for this impairment are few and inadequate.

One of the cardinal features of wound healing is the formation of new small blood vessels at the site
of injury. One of the ways in which this happens is by bone marrow-derived progenitor cells called
Endothelial Progenitor Cells (EPCs), in a process known as vasculogenesis. Poor healing of diabetic
wound is characterized by impaired vasculogenesis. The process by which EPCs lead to the formation
of new blood vessels involves two important linksthe mobilization of EPCs from bone marrow into
circulation and the recruitment of EPCs from the circulation to the repair site. The cascade begins
when a vessel growth-promoting factor called VEGF (Vasoactive Endothelial Growth Factor) is
released by ischemic tissue, like a diabetic wound complicated by decreased blood flow. VEGF goes
to the bone marrow and activates an enzyme called nitric oxide synthase (NOS) which, as the name
suggests, produces a diffusible chemical called nitric oxide or NO. This increased NO leads to the
mobilization of EPCs from the bone marrow into the circulation. Once in the circulation, they need to
migrate to the site of repair. This is dependent on the increased levels of a chemical called SDF-1
which attracts the EPCs to the workplace (see Fig 1). At the wound site, they begin the process of
neovascularization (i.e., formation of new blood vessels) and healing. Now what goes wrong with
chain of events in diabetes was unknown, that is, until recently.

Katherine Gallagher and colleagues have found that both these links-EPC mobilization and
recruitment-are defective in diabetic mice as compared to healthy ones. Further, mending these
defects by specific therapeutic interventions led to marked improvement in wound healing.
Working on the first step, the researchers showed that the levels of the enzyme NOS, which is
needed for NO production and EPC mobilization, are reduced in the bone marrow of diabetic mice as
compared to healthy ones (see Fig 1). This led to a reduction, by as much as 50 percent, in the
number of circulating EPCs. They then tested the effect of hyperoxia (excessive oxygen in the system
due to exposure to high pressure oxygen) which has been shown to stimulate NOS in some tissues on
the diabetic mice. And sure enough, hyperoxia led to a marked increase in the bone marrow-NO
levels and a consequent fivefold increase in the number of circulating EPCs (when NOS was inhibited
before hyperoxia administration, no increase in EPC mobilization was observed, thus underscoring
the importance of this enzyme in this pathway). However, even when the number of circulating EPCs
was increased, there was no significant change in the number of EPCs reaching the wound site. This
is where the second part of the story comes in.

After being mobilized into the circulation, EPCs need to be called to the site of action, which is done
by increased levels of the chemical SDF-1. Gallagher and colleagues found that in diabetic mice,
SDF-1 levels were reduced by as much as 50 percent (see Fig 1). Predictably, injection of SDF-1 into
the wound led to an increase in the number of wound EPCs.

Even better, when both hyperoxia and SDF-1a were given together, a synergistic effect was produced,
thus supporting the conclusion that mobilization of EPCs into the circulation along with their
recruitment to the wound site lead to improved wound healing in diabetics (see fig 2).

This study opens exciting new vistas for both further basic research and therapeutic innovations. In
the past too, hyperoxia based therapies have been used for diabetic patients, but they have provided
inconsistent results. That may be due to the fact that such interventions target only one leg of the
EPC response, the mobilization. Gallagher and colleagues demonstrate that the recruitment of EPCs
is integral to EPC-mediated healing and targeting just one aspect of the latter would be inadequate.
Therefore, future therapies for ischemic complications will have to be based on correcting multiple
deficits simultaneously. Therapeutic interventions, including correcting both EPC activation via
hyperoxia and EPC homing via administration of SDF-1 may significantly accelerate diabetic wound
healing by correcting the EPC deficit inherent to diabetic wounds, write Harold Brem and Marjana
Tomic-Canic in an accompanying commentary to the article.