549 Regen. Med. (2015) 10(5), 549–562 ISSN 1746-0751
part of
Research Article
10.2217/RME.15.24 © 2015 Future Medicine Ltd
Aim: Secondary lymphedema is observed in common after postmalignancy
treatment of the breast and the gynecologic organs but effective therapies are not
established. Adipose-derived stem cells (ADSCs), which are pluripotent, regenerative
in local injection, are tested for murine hindlimb secondary lymphedema by
regenerative method. Methods & results: Mice were divided into four groups: no
ADSCs, 1 × 10
6
ADSCs, 1 × 10
5
ADSCs and 1 × 10
4
ADSCs (each group, n = 20) in a
stringent surgical resection and irradiation. Circumferential measurement, lymphatic
flow assessment and quantification of lymphatic vessels were performed. Results:
The numbers of lymphatic vessels by LYVE-1 immunohistochemistry, and VEGF-C-
or VEGFR3-expressing cells were significantly increased in transplanted groups
(p < 0.05). Conclusion: ADSCs can restore the lymphatic vascular network in secondary
lymphedema with increased collecting vessels.
Keywords:adipose-derivedstemcell•lymphangiogenesis•mouse•radiation•secondary
lymphedema•surgery•VEGF-C•VEGFR3
Lymphedema demonstrates chronic inflam-
mation and the impairment of lymphatic sys-
tems in terms of the drainage and circulation
of interstitial protein-rich fluid [1] and usually
a progressive condition for which no complete
treatment may exist. Lymphedema generally
requires combined conservative treatments,
currently based on drug therapy, conservative
therapy such as physiotherapy [2] , compres-
sion and occasionally surgery. Lymphedema
is subcategorized into primary and second-
ary types depending on the etiology. Pri-
mary lymphedema is caused by anatomic or
functional defects in the lymphatic system,
involving several genes including VEGFR3
and VEGF-C [3,4] . On the other hand, sec-
ondary lymphedema is acquired as a result
of trauma, surgery, radiotherapy, infection
or a combination of these. Cancer therapy
with radical surgical lymph node dissection
and radiotherapy may result in impairment
of lymphatic vessels. Approximately 30% of
patients who undergo breast cancer surgery
may develop lymphedema and 6% of cases
of sentinel navigation surgery in the breast
progress to lymphedema [5,23] .
In gynecologic cancers, 10% to almost
30% of patients may develop lymphedema,
depending on the cancer type, age and sur-
gical approach, and postoperative radiation
increases the proportion of lymphedema
to over 35% [6,7] . A 13% of 1243 patients
treated for endometrial cancer developed
lymphedema at 3–5-year follow-up. More
than 15 lymph nodes removal and addi-
tional risk factors are determinant factor for
development of secondary lymphedema and
requiring affordable management of pain
and discomfort [8] .
Patients with breast and gynecological
cancers show lymphatic vessel damage by sur-
gery, infection and radiation therapy. Breast
cancer related lymphedema may be caused by
slower drainage in the subcutaneous tissue
and in the muscle and abnormal lymphatic
systems [9] . A total of 16% of patients with
both sentinel lymph node biopsy and axillary
lymph node dissection demonstrated lymph-
Adipose-derived stem cell transplantation
for therapeutic lymphangiogenesis in a
mouse secondary lymphedema model
Shuhei Yoshida
1
, Rodrigo
Hamuy
1
, Yuuichi Hamada
2
,
Hiroshi Yoshimoto
1
, Akiyoshi
Hirano
1
& Sadanori Akita*
,1
1
DivisionofPlastic&Reconstructive
Surgery,DepartmentofDevelopmental
&ReconstructiveMedicine,Nagasaki
UniversityGraduateSchoolof
BiomedicalSciences,1–7–1Sakamoto,
Nagasaki,8528501,Japan
2
DivisionofPlastic&Reconstructive
Surgery,OitaSanaiMedicalCenter,
1213Ichi,Oita870-1151,Japan
*Authorforcorrespondence:
Tel.:+81958197327
Fax:+81958197330
akitas@hf.rim.or.jp
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