Endothelial progenitor cells: from senescence to rejuvenation

Abstract

Discovered more than 15 years ago, endothelial progenitor cells attract both basic and translational researchers. It has become clear that they represent a heterogeneous population of endothelial colony-forming cells, early or late outgrowth endothelial cells, or blood outgrowth endothelial cells, each characterized by differing proliferative and regenerative capacity. Scattered within the vascular wall, these cells participate in angiogenesis and vasculogenesis and support regeneration of epithelial cells. There is growing evidence that this cell population is impaired during the course of chronic cardiovascular and kidney disease when it undergoes premature senescence and loss of specialized functions. Senescence-associated secretory products released by such cells can affect the neighboring cells and further exacerbate their regenerative capacity. For these reasons, adoptive transfer of endothelial progenitor cells is being used in more than 150 ongoing clinical trials of diverse cardiovascular diseases. Attempts to rejuvenate this cell population either ex vivo or in situ are emerging. The progress in this field is paramount to regenerate the injured kidney.

Keywords: Stress-induced premature senescence (SIPS); cell therapy; regeneration; rejuvenation therapy; senescence-associated secretory products (SASP).

Figure 1

Distribution of stem and progenitor cells in all layers of the vascular wall intima, media, adventitia and perivascular adipose tissue.

Figure 2

Targets of senenscence-associated secretory products (SASP) of senescent cells. In contrast to the normal secretome of EPC and endothelial cells, SASP is enriched in IL-6, IL-8, TGF-α, galectin-3, IGFBP-3,-4, and -6, and MIC-1, which compromise functions of all neighboring cells in the paracrine fashion.

Figure 3

EPC and VESC are engaged in the maintenance of vascular and epithelial homeostasis. Development of SIPS in the course of chronic kidney disease (CKD) perturbs both of these functions, thus disrupting homeostatic regulation and producing a pro-inflammatory microenvironment, which in turn further compromises functions of other stem and mature cells, potentially aggravating the primary disease process and derailing regeneration. Thick arrows indicate the presumed inhibitory functions of prematurely senescent cells. Boxed area introduces “cell therapy” and “cell-free therapy”.

Figure 4

Pathways responsible for the development of SIPS. Initiating noxious stressors induce permeabilization of the lysosomal membrane, leakage of lysosomal enzymes and degradation of sirtui-1, which in turn results in the activation of mTORC and inhibition of autophagic degradation of misfolded proteins, dysfunctional mitochondria and peroxisomes. Developing endothelial dysfunction is associated with glutamine depletion, which, depending on the biological context, may activate or inhibit mTORC. Importantly, supplemental glutamine reverses endothelial dysfunction and restores metabolism in mice with experimental model of chronic inhibition of endothelial NO synthase.

Figure 5

Examples of “cell-therapy” and “cell-free rejuvenating therapy” in mice with the model of type 2 diabetes (db/db mouse). General schema of the experiemnts (a). Db/db mice adoptively transferred with the bone marrow EPC obtained from control db/m mice (dbTxm) exhibited significant improvement of macro- and microvasculopathy, as opposed to db/db mice adoptively transferred with EPC obtained from db/db mice (b and c). The similar effect was observed after chronic therapy with the seleno-organic antioxidant and peroxinitrite scavenger ebselen. Macrovasculopathy was also improved by adoptive transfer of db/db EPC pretreated in culture with ebselen (Txdb-Ebs-ex vivo). Modified from ref .