The controversial origin of pericytes during angiogenesis – Implications for cell-based therapeutic angiogenesis and cell-based therapies

Abstract

Pericytes reside within the basement membrane of small vessels and are often in direct cellular contact with endothelial cells, fulfilling important functions during blood vessel formation and homeostasis. Recently, these pericytes have been also identified as mesenchymal stem cells. Mesenchymal stem cells, and especially their specialized subpopulation of pericytes, represent promising candidates for therapeutic angiogenesis applications, and have already been widely applied in pre-clinical and clinical trials. However, cell-based therapies of ischemic diseases (especially of myocardial infarction) have not resulted in significant long-term improvement. Interestingly, pericytes from a hematopoietic origin were observed in embryonic skin and a pericyte sub-population expressing leukocyte and monocyte markers was described during adult angiogenesis in vivo. Since mesenchymal stem cells do not express hematopoietic markers, the latter cell type might represent an alternative pericyte population relevant to angiogenesis. Therefore, we sourced blood-derived angiogenic cells (BDACs) from monocytes that closely resembled hematopoietic pericytes, which had only been observed in vivo thus far. BDACs displayed many pericytic features and exhibited enhanced revascularization and functional tissue regeneration in a pre-clinical model of critical limb ischemia. Comparison between BDACs and mesenchymal pericytes indicated that BDACs (while resembling hematopoietic pericytes) enhanced early stages of angiogenesis, such as endothelial cell sprouting. In contrast, mesenchymal pericytes were responsible for blood vessel maturation and homeostasis, while reducing endothelial sprouting.Since the formation of new blood vessels is crucial during therapeutic angiogenesis or during integration of implants into the host tissue, hematopoietic pericytes (and therefore BDACs) might offer an advantageous addition or even an alternative for cell-based therapies.

Pericytes improve locomotor recovery after spinal cord injury in male and female neonatal rats

“…This work provides proof of concept that naïve pericytes may be useful in improving outcomes after SCI 38 . The positive effect of pericyte injection on locomotor recovery is consistent with results of pericyte cell therapy in peripheral and retinal pathologies.…”

Vascular Endothelial Cell Biology: An Update

“…The capillary plexus is remodeled by sprouting, microvascular growth and fusion into a mature and functional vascular bed during angiogenesis [126,127]. Angiogenesis also includes vessel penetration into avascular tissue regions and is critically dependent on the essential interactions among EC, pericytes [128], inflammatory cells such as macrophages [129,130] and other adjacent cells associated with the extracellular matrix (ECM) and vascular basement membrane (BM). In contrast to embryonic development, adult angiogenesis is closely related to a number of physiologically relevant processes e.g., wound healing [131,132] or pathophysiological conditions like inflammatory disorders [133], cancer [134] or diabetes mellitus [135,136] (Figure 7).…”

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

“…During angiogenesis, pericytes are reported to be recruited from the bone marrow as well as brain parenchyma in response to the PDGF-BB secreted from endothelial cells (Rajantie et al, 2004;Song et al, 2005;Kokovay et al, 2006;Gaengel et al, 2009). On the other hand, pericytes induce endothelial cell sprouting and stabilization via secreting TGFβ, VEGF, and ANGPT1 (Paik et al, 2004;Durham et al, 2014;Teichert et al, 2017;Blocki et al, 2018). Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis including microaneurysm (Lindahl et al, 1997;Hellström et al, 2001).…”