Blood flow-induced angiocrine signals promote organ growth and regeneration

Abstract

Recently, we identified myeloid-derived growth factor (MYDGF) as a blood flow-induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano-elastic properties and flow-mediated alterations in the organ-specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal.

Keywords: Myeloid‐derived growth factor (MYDGF); angiocrine signals; blood flow; liver; organ growth; regeneration.

FIGURE 1

Blood flow‐induced angiocrine signals governing organ growth after partial organ resection. (A) Under normal conditions, the blood in the liver flows from the portal venule and hepatic arteriole through the liver sinusoids to the central venule or vein. The apical surface of the LSECs faces the bloodstream, and the LSECs are separated from hepatocytes by the space of Disse. After a PHx, the sinusoids are vasodilated and, therefore, the LSECs are mechanically stretched. This stimulation triggers the release of several angiocrine signals, that is HGF, MYDGF and IL‐6. Angiocrine signals promote hypertrophy and hyperplasia of the liver. A similar mechanism might take place in lung and kidney. (B) In the lung, ECs also face the bloodstream with their apical cell surface. After PNX, mechanical forces (including those induced by the altered blood flow) cause stretching of alveolar epithelial cells and ECs. Angiocrine signals, that is MMP14 and HB‐EGF, are released to contribute to the growth of the lung. (C) In the kidney, ECs also face the bloodstream with their apical surface. After nephrectomy, hemodynamic changes occur in the remaining kidney, which may trigger the release of angiocrine signals. For the kidney, HGF has been identified as an angiocrine signal. EC, endothelial cells; HB‐EGF, heparin‐binding epidermal growth factor; HGF, hepatocyte growth factor; IL‐6, interleukin‐6; MMP14, matrix metalloprotease 14; MYDGF, myeloid‐derived growth factor; LSEC, liver sinusoidal endothelial cells; PHx, partial hepatectomy;PNX, pneumonectomy.

FIGURE 2

MYDGF versus HGF concentrations after liver surgery in humans and mice. Analysis of serum MYDGF (A) or HGF (B) levels after stage 1 of in‐situ split liver surgery, n = 1 male patient. Analysis of MYDGF (C) or HGF (D) levels in mouse hepatic ECs isolated from the remaining right liver lobe at different time points after PHx. N = 5 (0 and 3 h), n = 4 (6 and 12 h) and n = 3 mice (24 h). Data are presented as mean ± SEM. p‐values were calculated using one‐way ANOVA followed by Dunnett's post hoc test (C, D). Part of this Figure was published in ^{[ 55 ]}, which is licensed under the Creative Commons Attribution 4.0 International License. EC, endothelial cells; HGF, hepatocyte growth factor; MYDGF, myeloid‐derived growth factor; PHx, partial hepatectomy.

FIGURE 3

General model: Hemodynamic changes due to partial organ loss promote organ growth via mechanically‐released angiocrine signals. After partial organ loss, such as after partial hepatectomy, pneumonectomy or nephrectomy, the respective intra‐organ blood flow increases. The hemodynamic changes lead to mechanical stretching of the organ‐specific microvascular ECs, which subsequently release angiocrine signals to induce hypertrophy and/or hyperplasia of the tissue cell types, thus promoting organ growth. EC, endothelial cells.