Experimental Lymphedema: Can Cellular Therapies Augment the Therapeutic Potential for Lymphangiogenesis?

Experimental Lymphedema:  Can Cellular Therapies Augment the Therapeutic Potential for Lymphangiogenesis?

2012

Stanley G. Rockson

Journal of the American Heart Association

Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells.

Therapeutic lymphangiogenesis with implantation of adipose-derived regenerative cells.

Aug 2012

Shimizu Y, Shibata R, Shintani S, Ishii M, Murohara T.

Source

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

BACKGROUND:

Lymphedema is one of the serious clinical problems that can occur after surgical resection of malignant tumors such as breast cancer or intra-pelvic cancers. However, no effective treatment options exist at present. Here, we report that implantation of adipose-derived regenerative cells (ADRCs) can induce lymphangiogenesis in a mouse model of reparative lymphedema.

METHODS AND RESULTS:

 ADRCs were isolated from C57BL/6J mice. To examine the therapeutic efficacy of ADRC  implantation in vivo, we established a new mouse model of tail lymphedema. Lymphedema was improved significantly by local injection of ADRCs. Histological analysis revealed that lymphatic capillary density was greater in the ADRC group than in the phosphate-buffered saline control group. Tissue expression of vascular endothelial growth factor C mRNA and plasma levels of vascular endothelial growth factor C  ADRCs released vascular endothelial growth factor C, which directly stimulated lymphangiogenesis. Implantation of ADRCs also enhanced recruitment of bone marrow-derived M2 macrophages, which served as lymphatic endothelial progenitor cells.

CONCLUSIONS:

Implantation of autologous ADRCs could be a useful treatment option for patients with severe lymphedema.

PubMed

Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration.

Sept 2012

Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, Lee HN, Kim KE, Lee S, Park EK, Maeng YS, Kim NY, Ladner RD, Petasis NA, Koh CJ, Chen L, Lenz HJ, Hong YK.

Source

Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy St. NRT6501, Mail Code 9601, Los Angeles, CA, 90033, USA.

Abstract

Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs.Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. 

Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57(KIP2) by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo.

Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. 

Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.

Springerlink