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Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.

ABSTRACT: Lymph is returned to the blood circulation exclusively via four lymphovenous valves (LVVs). Despite their vital importance, the architecture and development of LVVs is poorly understood. We analyzed the formation of LVVs at the molecular and ultrastructural levels during mouse embryogenesis and identified three critical steps. First, LVV-forming endothelial cells (LVV-ECs) differentiate from PROX1(+) progenitors and delaminate from the luminal side of the veins. Second, LVV-ECs aggregate, align perpendicular to the direction of lymph flow and establish lympho-venous connections. Finally, LVVs mature with the recruitment of mural cells. LVV morphogenesis is disrupted in four different mouse models of primary lymphedema and the severity of LVV defects correlate with that of lymphedema. In summary, we have provided the first and the most comprehensive analysis of LVV development. Furthermore, our work suggests that aberrant LVVs contribute to lymphedema.

SUBMITTER: Geng X

PROVIDER: S-EPMC4688075 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.

Geng Xin X Cha Boksik B Mahamud Md Riaj MR Lim Kim-Chew KC Silasi-Mansat Robert R Uddin Mohammad K M MKM Miura Naoyuki N Xia Lijun L Simon Alexander M AM Engel James Douglas JD Chen Hong H Lupu Florea F Srinivasan R Sathish RS

Developmental biology 20151102 1

Lymph is returned to the blood circulation exclusively via four lymphovenous valves (LVVs). Despite their vital importance, the architecture and development of LVVs is poorly understood. We analyzed the formation of LVVs at the molecular and ultrastructural levels during mouse embryogenesis and identified three critical steps. First, LVV-forming endothelial cells (LVV-ECs) differentiate from PROX1(+) progenitors and delaminate from the luminal side of the veins. Second, LVV-ECs aggregate, align ...[more]

PMID: 26542011

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Project description:Lymphedema (LD) is characterized by the accumulation of protein-rich interstitial fluid, lipids and a significant inflammatory cell infiltrate in the limb. It causes a significant morbidity and is a common disabling disease affecting more than 150 million people worldwide, however there is no yet curative treatment. In this study, we found that LD tissues from patients exhibit inflamed gene expression profile compared to their normal arm. This was next confirmed by a lipidomic analysis that revealed severe decrease in arachidonic acid-derived lipid mediators generated by the 15-lipoxygenase (15-LO) in lymphedematous arms. Using a mouse model of lymphedema, we reproduced the etiology of the human pathology including the loss of specialized pro-resolving lipid mediators that play essential role in resolution of inflammation. This was associated with a lack of nonlymphoid PPAR-positive regulatory T cells (Treg) recruitment in the injured limb adipose tissue. Importantly, we identified the lymphatic endothelial 15-LO as responsible for the chemoattraction and survival of this Treg subpopulation. These results were confirmed by an aggravation of LD and degradation of the lymphatic network in an original transgenic mouse model in which ALOX15 gene has been selectively deleted in the lymphatic system (ALOX15lecKO). Importantly, this phenotype was rescued by the injection of ALOX15-expressing lentivectors. These results provide evidence that lymphatic 15-LO may represent a novel therapeutic target for LD by serving as a mediator of nonlymphoid Treg cell population invasion into lymphedematous adipose tissue to resolve inflammation. Experimental workflow: To broadly identify gene expression signatures associated to secondary LD, we performed bulk-RNA sequencing on dermolipectomy tissue samples from women who developed LD after breast cancer. Four patient biopsies (normal arm and LD arm in each patient) were studied and the differential expression analysis (DEseq) followed by a protein-coding RNA profiling.

Dataset Information

Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.

Publications

Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.

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