Abstract
The reduced number of circulating stem/progenitor cells that is found in chronic kidney disease (CKD) patients may contribute to impaired angiogenic repair and decreased capillary density in the heart. Cell therapy with bone marrow-derived cells (BMDCs) has been shown to induce positive effects on the microvasculature and cardiac function, most likely due to secretion of growth factors and cytokines, all of which are present in the conditioned medium (CM); however, this is controversial. Here we showed that treatment with BMDC or CM restored vascular density and decreased the extent of fibrosis in a rat model of CKD, the 5/6 nephrectomy. Engraftment and differentiation of exogenous BMDCs could not be detected. Yet CM led to the mobilization and infiltration of endogenous circulating cells into the heart. Cell recruitment was facilitated by the local expression of pro-inflammatory factors such as the macrophage chemoattractant protein-1, interleukin-6, and endothelial adhesion molecules. Consistently, in vitro assays showed that CM increased endothelial adhesiveness to circulating cells by upregulating the expression of adhesion molecules, and stimulated angiogenesis/endothelial tube formation. Overall, our results suggest that both treatments exert vasculoprotective effects on the heart of uremic rats by stimulating endogenous repair mechanisms.
Highlights
Chronic kidney disease (CKD) is closely associated with cardiovascular disease and a high risk of death[1, 2]
Confirming our previous results, we found that experimental uremia, i.e., 5/6 nephrectomy (Nx), induces a 20% reduction in heart capillary density compared with a sham operation, as observed by the reduced number of capillaries per cardiomyocyte stained with an endothelial cell marker 14 days after surgery (Fig. 1a–b)
To track possible cell engraftment in vivo, we induced Nx in Lewis rats, and these animals were treated with Bone marrow-derived cells (BMDCs) that were isolated from transgenic eGFP-Lewis rats
Summary
Chronic kidney disease (CKD) is closely associated with cardiovascular disease and a high risk of death[1, 2]. The therapy’s positive effect on the microvasculature was observed in experimental studies that showed increased capillary density in an ischemic hind limb model after BMDC administration Engraftment of these cells into the ischemic area and differentiation into cardiac cells or endothelial cells appear to be minimal or even absent[17, 18]. Angiogenesis is regulated by different growth factors[21, 22] and by the recruitment of marrow-derived endothelial as well as hematopoietic cells (collectively defined here as endogenous BMDCs)[23, 24] Once they infiltrate the target tissue, these cells function in a paracrine fashion to regulate a complex process that involves inflammation, angiogenesis, and tissue repair[25,26,27]. Considering that (1) CKD is associated with a decreased number of circulating progenitor cells, (2) this reduction represents a higher risk of future cardiovascular events and cardiovascular death as observed in a meta-analysis[28], and (3) these cells (and their CM) are able to promote angiogenesis and vascular repair, it is reasonable to propose therapy with BMDCs as an alternative to replenish the stem and progenitor pool in CKD, or mimic their endocrine mode of action using therapy with the CM
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