Lymphedema affects between 38% and 89% of millions of breast cancer (BCa) survivors in the United States, and it is one of the least researched, relatively underestimated, and most poorly understood complications of cancer or its treatment. BCa-linked lymphedema occurs as a result of lymphatic vessel destruction during the removal of lymph nodes or radiation therapy, and it can lead to debilitating limb swelling, chronic inflammation, tissue fibrosis, and increased susceptibility to infection. This research addresses the overarching challenge of conquering the problems of BCa-linked lymphedema. Successful development of our proposed regenerative therapy will significantly reduce the morbidity associated with cancer-linked lymphedema. The rationale for this proposal is based on our new findings where two peptide hormones—adrenomedullin (ADM) and intermedin (IMD)—and their cognate receptors, the calcitonin receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs), are required for lymphatic vessel development and will be sufficient and necessary to reprogram adult tissue stem cells from patients to functional lymphatic endothelial cells (LECs). These LECs can form new lymphatic vessels for restoring lymphatic circulation in patients with lymphedema. However, wildtype (wt) ADM and IMD have shorter half-lives in vivo; thus, we hypothesize that the newly invented stable CLR-RAMP agonists (designated sCLR agonists), which are stable ADM and IMD analogs, will be more potent than wt hormone peptides in combating lymphedema. Because BCa survivors may be deprived of endothelial progenitor or stem cells that are essential for the regeneration of lymphatic vessels, we further hypothesize that the combination therapy that integrates sCLR agonists and stem cells will be the most efficient approach to prevent the occurrence of, or to reduce the debilitating effects of lymphedema. The objectives of this project are to overcome the problems of BCa-linked lymphedema by applying novel sCLR agonists and adult adiposetissue stem cells (ASCs) or induced pluripotent stem cells (iPSCs) to regenerate LECs to restore lymphatic circulation in vivo, and to understand the mechanisms for sCLR agonists-mediated reprogramming of LECs from ASCs or iPSCs for reviving a functional lymphatic system. We plan to achieve our Aims by studying the efficacy of a combination therapy that combines sCLR agonists and ASCs or iPSCs in the mouse lymphedema models. To address the study hypothesis, we will focus on two Specific Aims: (1) to determine the efficacy of combined treatment with sCLR agonists and ASCs or iPSCs in reconstructing lymphatic circulation in vivo; and (2) to elucidate the signaling mechanisms whereby sCLR agonists regulate reprogramming of LECs from ASCs or iPSCs. In summary, this study is required to validate the utility of novel combination therapies. Also, the results of this mechanistic study will provide significant insight into the signaling mechanisms underlying sCLR agonists-promoted reprogramming of LECs from ASCs or iPSCs for regenerating a functional lymphatic system, and to contribute to optimizing therapeutic applications of sCLR agonists for healing lymphedema.