Examining the Paracrine Effects of Exosomes in Cardiovascular Disease and Repair

Figures

• 

  Figure 1. Extracellular vesicle subtypes. Extracellular vesicles are divided into 3 categories based on size, contents, and route of formation. Exosomes, the smallest, originate within multivesicular bodies and carry RNAs, proteins, and lipids. Microvesicles, the next largest, form through outward pinching off of the plasma membrane and also contain RNAs, proteins, and lipids. Apoptotic bodies are formed from dying cells as the plasma membrane blebs to recycle contents. Apoptotic bodies are variable in size and contain cell debris, genomic DNA (gDNA), and proteins.

• 

  Figure 2. The formation and fates of multivesicular bodies. During endocytosis, the plasma membrane (PM) buds inward, filling with cytoplasmic contents and forming the early endosome. Surface proteins may be retained throughout endocytosis. The early endosome matures into the late endosome. This membrane further buds inward with the aid of the endosomal sorting complex required for transport (ESCRT), forming intraluminal vesicles. Once filled with these vesicles (now known as exosomes), the late endosome becomes the multivesicular body, which may either deliver its contents to the lysosome for degradation or fuse with the PM to secrete exosomes.

• 

  Figure 3. Paracrine effects in disease exerted by cardiovascular exosomes. Cardiovascular secreted exosomes exert diverse effects on their destination cells, considering the cell type of origin, exosomal contents, and the conditions of release. Cardiac fibroblast–derived exosomes have been associated with pathology because of their transference of microRNA (miR) 21, which led to the induction of cardiac hypertrophy.70 The effects of cardiomyocyte‐derived exosomes were either proangiogenic82 or antiangiogenic,89 dependent on the conditions of release, which affected their miR cargo. Cardiomyocyte‐secreted exosomes were also found to be involved in the transfer of functional angiotensin II type 1 receptors (AT1Rs) under conditions of stress12 and involved in HSP90 (heat shock 90‐kDa protein)–dependent regulation of collagen synthesis in fibroblasts in models of hypertrophy.83 Serum and plasma exosomes arise from a variety of cell sources, and the diversity of their effects results from the disease status and conditions of release. Diabetic serum exosomes fail to stimulate ERK1/2‐protective signaling in cardiomyocytes,90 whereas plasma exosomes from healthy controls could stimulate ERK1/2…

• 

  Figure 4. Using induced pluripotent stem cells (iPSCs) to study exosomal communication between cardiovascular cell types. Patient‐ or disease‐specific iPSCs can be differentiated into multiple cell types including cardiomyocytes, endothelial cells, or smooth muscle cells. These derived cells can be used to collect and profile exosomes (exos) or to assess cell‐type–specific exosomal effects on recipient cell function. iCM indicates iPSC‐derived cardiomyoycte; iEC, iPSC‐derived endothelial cell; iSMC, iPSC‐derived smooth muscle cell; LDL, low‐density lipoprotein.

• 

  Figure 5. Example of using induced pluripotent stem cell (iPSC)–derived cells to investigate cell‐ or disease‐specific exosome cargo. Exosomes were isolated from wild‐type (WT) and dystrophin‐deficient (Dys)‐iPSC‐derived cardiac and skeletal myocyte‐conditioned media using an isolation reagent by Thermo Fisher. A, Isolated exosome size (50 nm) and morphology was confirmed by electron microscopy. B, WT and Dys cardiac and skeletal myocyte exosomes display differential microRNA (miR) profiles, as shown by polymerase chain reaction array analysis. hsa indicates homo sapiens; iCM, iPSC‐derived cardiomyocytes; iSkM, iPSC‐derived skeletal muscle cells; let, part of the lethal‐7 gene family.