Adipocyte cell therapy targeting bone morphogenetic protein signaling alleviates fibroadipose tissue deposition in secondary lymphedema.

Abstract

Secondary lymphedema is a chronic disease affecting an isolated limb following lymph node resection for cancer treatment. Management options are limited and onerous, leading to near-universal progression to subcutaneous fibroadipose tissue deposition. Here, we identify bone morphogenetic protein ligands (BMPs) as mediators of fibroadipose tissue deposition through in vitro experiments with human lymphedema fluid and BMP-specific inhibitor. Systemic in vivo delivery of BMP inhibitor reduces fibroadipose tissue deposition in a mouse model of hindlimb secondary lymphedema. Considering systemic delivery may be undesirable for an anatomically-isolated disease, we engineered a cell therapy using purified adipocytes, aiming for clinical translation in a resource- and time- constrained environment requiring only mechanical manipulation. We then devised a strategy for gene delivery into adipocytes and verified the secretion of the recombinant peptide inhibitor of BMP ligands. Upon in vivo delivery of the engineered adipocytes, we verified secretion of the BMP inhibitor and a reduction in fibroadipose tissue deposition in the mice hindlimb. Our findings highlight BMPs as signaling mediators for fibroadipose tissue deposition and provide a blueprint for a cell therapy using genetically-modified adipocytes for local drug delivery. This approach may be in a point-of-care strategy and potentially be amenable to various conditions.