Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema
Abstract
1. Introduction
2. Pathophysiology of Secondary Lymphedema
3. Pharmacotherapy for Lymphedema
3.1. Doxycycline
3.2. Leukotriene B4 Inhibitors (Ketoprofen, Ubenimex)
3.3. Selenium
3.4. Synbiotic Supplements
3.5. CD4+ T Cell Suppressants (Tacrolimus, Anti-IL-4/IL-13 Antibodies, Fingolimod)
3.6. TGF-β Inhibitors (Anti-TGF-β Antibody, Vactosertib, LY-364947)
4. Cell-Based Therapy for Lymphedema
4.1. Animal Studies
4.2. Clinical Studies
5. Discussion
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ADRC | adipose-derived regenerative cell |
ASC | adipose-derived mesenchymal stem/stromal cell |
CCL | C–C chemokine ligand |
CCR | C–C chemokine receptor |
CLA | cutaneous leukocyte antigen |
CRP | C-reactive protein |
DAMPs | danger-associated molecular patterns |
DC | dendritic cell |
eNOS | endothelial nitric oxide synthase |
GFP | green fluorescent protein |
HMGB1 | high-mobility group box 1 |
IFN | interferon |
IL | interleukin |
IL2-c | IL-2/anti-IL-2 complex |
iNOS | inducible nitric oxide synthase |
LEC | lymphatic endothelial cell |
LT | leukotriene |
LYVE-1 | lymphatic vessel endothelial hyaluronan receptor 1 |
MSC | mesenchymal stem/stromal cell |
QOL | quality of life |
RT | radiation therapy |
SVF | stromal vascular fraction |
Th | helper T cell |
TNF | tumor necrosis factor |
TGF | transforming growth factor |
Treg | regulatory T cell |
VEGF | vascular endothelial growth factor |
VLNT | vascularized lymph node transfer |
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Author | Animal | Model of Lymphedema | Cell | Treatment | Control Group(s) | Outcomes |
---|---|---|---|---|---|---|
(Transplantation of MSCs) | ||||||
Conrad et al. 2009 [35] | Female C57BL/6 mouse | Tail model Surgery alone | p53-/- mice origin BMSC |
|
|
|
Hwang et al. 2011 [36] | Female BALB/c mouse | Hindlimb model Surgery alone | Human origin ASC, PKH-26-labeled (commercial item) |
|
|
|
Zhou et al. 2011 [37] | Female/ male New Zealand white rabbit | Hindlimb model Surgery + RT 60Co γ-ray irradiation, 2000 cGy, 3 days after surgery | New Zealand white rabbit origin BMSCs (CD29+, CD44+, CD11b−, CD45−) |
|
|
|
Shimizu et al. 2012 [38] | Male C57BL/6J mouse | Tail model Surgery alone | Mouse inguinal fat pad origin ADRC |
|
|
|
Ackerman et al. 2015 [39] | Male C57BL/6 mouse | Tail model Surgery alone | Mouse inguinal fat pad origin ASC (passage 3, CD31−, CD45−, CD29+, CD90+) |
|
|
|
Yoshida et al. 2015 [40] | Male C57BL/6J mouse | Hindlimb model Surgery + RT X-ray irradiation, 30 Gy, 1 week before surgery | Mouse intra-abdominal and -inguinal origin ASC (up to 5 passages) |
|
|
|
Hayashida et al. 2017 [41] | Male C57BL6J mouse | Hindlimb model Surgery + RT X-ray irradiation, 30 Gy, 7 days before surgery | Mouse intra-abdominal and -inguinal origin ASC (from 1 to 3 passages) |
|
|
|
Beerens et al. 2018 [42] | Female athymic nude Foxn1 mouse | Forelimb model Surgery alone | Human bone marrow origin Multipotent adult progenitor cells (MAPCs) |
|
|
|
Bucan et al. 2020 [96] | Female C57BL/6 mouse | Hindlimb model Surgery + RT X-ray irradiation, 10 Gy × 2 times, 7 days before and 3 days after surgery | Mouse inguinal fat pad origin SVF (passage 0), ASC (passage 2) |
|
|
|
Dai et al. 2020 [43] | Female C57BL/6 mouse | Hindlimb model Surgery + RT Irradiated by 139Cs, 2.25 Gy × 2 times, 3 days before and 2 weeks after surgery | Mouse origin ASC (fleshly isolated, podoplanin-positive) |
|
|
|
Ogino et al. 2020 [44] | Male C57BL/6J mouse | Hindlimb model Surgery + RT X-ray irradiation, 30 Gy, 7 days before surgery | Mouse origin ASC (commercial item, passages 2–4) |
|
|
|
Nguyen et al. 2022 [45] | Female Sprague-Dawley rat | Hindlimb model Surgery + RT X-ray irradiation, 20 Gy, 7 ± 4 days after surgery | Rat inguinal fat pad origin SVF |
|
|
|
(Transplantation of LECs or Tregs) | ||||||
Park et al. 2013 [92] | Male BALB/c mouse | Hindlimb model Surgery + RT Irradiated by electron beam, 1500 cGy × 3 times, 5 days after surgery | Mouse gastrocnemius muscle origin Muscle-derived stem cells (MDSCs), after lymphatic differentiation (Prox-1+, VEGFR-3+, podoplanin+) |
|
|
|
Kawai et al. 2014 [93] | F344/N rnu/rnu nude rat | Tail model Surgery alone | Human origin LEC (CD31+, podoplanin+, LYVE-1+, Prox-1+) |
|
|
|
Gousopoulos et al. 2016 [23] | Female C57BL/6J mouse | Tail model Surgery alone | Mouse origin Treg (expanded by IL-2/anti-IL-2 antibody complex, CD4+, CD25+) |
|
|
|
Author | Participants | Cell | Treatment | Groups | Outcome | Side Effects |
---|---|---|---|---|---|---|
Hou et al. 2008 [97] | BCRL Undergone a breast cancer surgery and/no radiotherapy 5 years before | Autologous BMSC, collected from iliac crest bone marrow |
|
|
|
|
Maldonado et al. 2011 [98] | BCRL Patients with unilateral lymphedema secondary to mastectomy and lymphadenectomy with no active cancer in the last 5 years | Autologous bone marrow-derived CD34+ cell, collected from iliac crest bone marrow Initiated by subcutaneous injection of G-CSF for 3 days (300 μg/day) |
|
|
|
|
Toyserkani et al. 2017–2021 [99,100,101] | BCRL Recurrence-free disease for a minimum of 1 year, ISL stage I or II | Autologous ADRC, collected from abdomen or thigh adipose tissue (mean percentages of cells surface maker: CD34, 43.1%, CD90, 70.2%; CD31, 19.4%; CD73, 20.5%; CD45, 17.1%; CD235a, 33.1%) |
|
|
|
|
Ismail et al. 2017 [102] | Primary chronic lower limb lymphedema Primary lymphedema precox or tarda, up to stage III | Autologous BMMNC, collected from iliac crest bone marrow Initiated by subcutaneous injection of G-CSF for 5 days (600 μg/day) |
|
|
|
|
Ehyaeeghodraty et al. 2020 [103] | Primary lower limb lymphedema Grade I or II | Autologous PBMC, collected from antecubital vein blood Initiated by subcutaneous injection of G-CSF for 4 days (300 μg/day) |
|
|
|
|
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Ogino, R.; Yokooji, T.; Hayashida, M.; Suda, S.; Yamakawa, S.; Hayashida, K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. Int. J. Mol. Sci. 2022, 23, 7614. https://doi.org/10.3390/ijms23147614
Ogino R, Yokooji T, Hayashida M, Suda S, Yamakawa S, Hayashida K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. International Journal of Molecular Sciences. 2022; 23(14):7614. https://doi.org/10.3390/ijms23147614
Chicago/Turabian StyleOgino, Ryohei, Tomoharu Yokooji, Maiko Hayashida, Shota Suda, Sho Yamakawa, and Kenji Hayashida. 2022. "Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema" International Journal of Molecular Sciences 23, no. 14: 7614. https://doi.org/10.3390/ijms23147614
APA StyleOgino, R., Yokooji, T., Hayashida, M., Suda, S., Yamakawa, S., & Hayashida, K. (2022). Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. International Journal of Molecular Sciences, 23(14), 7614. https://doi.org/10.3390/ijms23147614