Sourcing of an Alternative Pericyte-Like Cell Type from Peripheral Blood in Clinically Relevant Numbers for Therapeutic Angiogenic Applications

Abstract

Autologous cells hold great potential for personalized cell therapy, reducing immunological and risk of infections. However, low cell counts at harvest with subsequently long expansion times with associated cell function loss currently impede the advancement of autologous cell therapy approaches. Here, we aimed to source clinically relevant numbers of proangiogenic cells from an easy accessible cell source, namely peripheral blood. Using macromolecular crowding (MMC) as a biotechnological platform, we derived a novel cell type from peripheral blood that is generated within 5 days in large numbers (10-40 million cells per 100 ml of blood). This blood-derived angiogenic cell (BDAC) type is of monocytic origin, but exhibits pericyte markers PDGFR-β and NG2 and demonstrates strong angiogenic activity, hitherto ascribed only to MSC-like pericytes. Our findings suggest that BDACs represent an alternative pericyte-like cell population of hematopoietic origin that is involved in promoting early stages of microvasculature formation. As a proof of principle of BDAC efficacy in an ischemic disease model, BDAC injection rescued affected tissues in a murine hind limb ischemia model by accelerating and enhancing revascularization. Derived from a renewable tissue that is easy to collect, BDACs overcome current short-comings of autologous cell therapy, in particular for tissue repair strategies.

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

“…249, 259 A recent study found that injection of blood-derived pericyte-like cells could rescue affected tissue by accelerating angiogenesis in a model of hind limb ischemia. 265 This result indicates that transplantation of pericyte progenitor cells may be a promising therapy for ischemia and could be possibly applied in ischemic stroke. More intriguingly, pericytes isolated from the ischemic regions of mouse or human brains reveal mesenchymal multi-lineage developmental properties when cultured under oxygen/glucose depriving environment, and could differentiate into both neural and vascular lineage cells.…”

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

“…In addition, they lacked MSCs markers such as CD146, thus were distinguishable from mesenchymal pericytes and expressed many angiogenic markers, such as VEGFR-1 and VEGFR-2. Although these cells had a monocytic origin, they exhibited a stable phenotype, as they could not be polarized towards M1 or M2 macrophages, nor did they exhibit macrophage features such as the ability to phagocytose [74]. Thus, although they were monocyte derived, they did not resemble macrophages.…”

“…Two years prior to this we published a study that described the isolation of a cell population from human adult peripheral blood closely resembling hematopoietic pericytes. Peripheral blood mononuclear cells (PBMCs) were cultured as a crude mixture under mixed macromolecular crowding (MMC) [74]. The crowded conditions that are normally found in vivo are emulated in vitro by the addition of polysucrose molecules [75,76].…”

“…Spindle-shaped cells were also subjected to various functional assays, and were demonstrated to co-localize with endothelial tubular networks and to dramatically enhance endothelial sprouting in vitro [74]. Thus, we termed this cell type blood-derived angiogenic cells (BDACs).…”

Response of encapsulated cells to a gelatin matrix with varied bulk and microenvironmental elastic properties

“…One of the major aims in regenerative medicine is to engineer biomaterials that can be readily transplanted to replace or to induce the regeneration of damaged tissues with the aim to resume the original function . For this purpose, biomaterials such as hydrogels are supplemented with progenitor cells that have a regenerative potential to form tissue in vitro or upon transplantation. Natural materials such as gelatin‐based hydrogels represent promising candidates for cellular carriers because of their tissue‐related biochemical, biophysical and biomechanical properties .…”