Statins reduce atherosclerotic events and cardiovascular mortality. Their side effects include memory loss, myopathy, cataract formation, and increased risk of diabetes. As cardiovascular mortality relates to plaque instability, which depends on the integrity of the fibrous cap, we hypothesize that the inhibition of the potential of mesenchymal stem cells (MSCs) to differentiate into macrophages would help to explain the long known, but less understood “non-lipid-associated” or pleiotropic benefit of statins on cardiovascular mortality. In the present investigation, MSCs were treated with atorvastatin or pravastatin at clinically relevant concentrations and their proliferation, differentiation potential, and gene expression profile were assessed. Both types of statins reduced the overall growth rate of MSCs. Especially, statins reduced the potential of MSCs to differentiate into macrophages while they exhibited no direct effect on macrophage function. These findings suggest that the limited capacity of MSCs to differentiate into macrophages could possibly result in decreased macrophage density within the arterial plaque, reduced inflammation, and subsequently enhance plaque stability. This would explain the non-lipid-associated reduction in cardiovascular events. On a negative side, statins impaired the osteogenic and chondrogenic differentiation potential of MSCs and increased cell senescence and apoptosis, as indicated by upregulation of p16, p53 and Caspase 3, 8, and 9. Statins also impaired the expression of DNA repair genes, including XRCC4, XRCC6, and Apex1. While the effect on macrophage differentiation explains the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.

Freshly isolated, uncultured, autologous adipose derived regenerative cells (ADRCs) have emerged as a promising tool for regenerative cell therapy. The Transpose RT system (InGeneron, Inc., Houston, TX, USA) is a system for isolating ADRCs from adipose tissue, commercially available in Europe as a CE-marked medical device and under clinical evaluation in the United States. This system makes use of the proprietary, enzymatic Matrase Reagent for isolating cells. The present study addressed the question whether the use of Matrase Reagent influences cell yield, cell viability, live cell yield, biological characteristics, physiological functions or structural properties of the ADRCs in final cell suspension. Identical samples of subcutaneous adipose tissue from 12 subjects undergoing elective lipoplasty were processed either with or without the use of Matrase Reagent. Then, characteristics of the ADRCs in the respective final cell suspensions were evaluated. Compared to non-enzymatic isolation, enzymatic isolation resulted in approximately twelve times higher mean cell yield (i.e., numbers of viable cells/ml lipoaspirate) and approximately 16 times more colony forming units. Despite these differences, cells isolated from lipoaspirate both with and without the use of Matrase Reagent were independently able to differentiate into cells of all three germ layers. This indicates that biological characteristics, physiological functions or structural properties relevant for the intended use were not altered or induced using Matrase Reagent. A comprehensive literature review demonstrated that isolation of ADRCs from lipoaspirate using the Transpose RT system and the Matrase Reagent results in the highest viable cell yield among published data regarding isolation of ADRCs from lipoaspirate.

It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither ‘fat stem cells’ nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.

Angiogenesis is a highly coordinated process essential for development, tissue homeostasis, and repair. In physiologic settings, endothelial cells remain quiescent until transient hypoxia- or injury-induced surges of VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), and other pro-angiogenic cues activate receptor tyrosine kinases, triggering MAPK (mitogen-activated protein kinase) and PI3K-AKT (phosphoinositide 3-kinase-AKT) cascades that drive sprouting, proliferation, migration, and vessel stabilization via pericyte recruitment and balanced Ang (angiopoietin)-Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2) signaling. In non-malignant pathologies, targeted pro-angiogenic therapies harness these mechanisms to restore perfusion in ischemic heart disease, chronic wounds, and neurovascular degeneration. In contrast, tumor-driven "malignant" angiogenesis subverts the same core pathways in both hypoxia-dependent and -independent manners. Oncogenic RAS (rat sarcoma)-RAF (rapidly accelerated fibrosarcoma)-MEK (MAPK/ERK kinase) and PI3K-AKT activity locks VEGFR2 (vascular endothelial growth factor receptor 2) Tyr1175 in a phosphorylated state, fueling unchecked endothelial proliferation and survival. Overexpression of integrin α_vβ₃ (alpha-v beta-3) and NRP2 (neuropilin 2) amplifies FAK (focal adhesion kinase)-Src-mediated invasion, while glycocalyx shedding and uneven pericyte coverage produce leaky vasculature. Transient vessel normalization upon VEGF blockade is followed by adaptive resistance via HIF (hypoxia-inducible factor)-driven upregulation of FGF2, Ang-2 (angiopoietin-2), and HGF (hepatocyte growth factor)/c-Met pathways, necessitating complex combination regimens. Rationally distinguishing when to inhibit versus augment angiogenesis is therefore clinically decisive, because cancers demand vascular suppression/normalization whereas ischemic and degenerative disorders benefit from controlled pro-angiogenic repair. We compared malignant and non-malignant angiogenesis at the molecular and clinical levels, critically appraising therapies, from VEGF antibodies and multitarget TKIs (tyrosine kinase inhibitors) to pro-angiogenic growth factors and drug-delivery platforms, and their respective biomarkers (Ang-2, soluble VEGFR2, VEGF isoform ratios). By explicitly linking pathway mechanics to therapeutic choice, dosing, and biomarker-guided selection, this review provides a comprehensive roadmap for tailoring angiogenesis-targeted interventions, either to restrain pathological neovascularization in cancer or to promote reparative vessel growth in ischemic and degenerative disease.

Background: Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. On the other hand, there are still misconceptions about these adipose-derived regenerative cells (ADRCs) that contain vascular-associated pluripotent stem cells (vaPS cells) in regenerative medicine. Methods: Based on our previous publications on this topic, we have developed a concept to describe the significance of the ADRCs/vaPS cells in the field of orthobiologics as briefly as possible and at the same time as precisely as possible. Results: The ADRCs/vaPS cells belong to the group of orthobiologics that are based on autologous cells. Because the latter can both stimulate a patient’s body's localized self-healing power and provide new cells that can integrate into the host tissue during the healing response when the localized self-healing power is exhausted, this group of orthobiologics appears more advantageous than cell-free orthobiologics and orthobiologics that are based on allogeneic cells. Within the group of orthobiologics that are based on autologous cells, enzymatically isolated, uncultured ADRCs/vaPS cells have several advantages over non-enzymatically isolated cells/microfragmented fat as well as over uncultured bone marrow aspirate concentrate and cultured cells (adipose-derived stem cells, bone marrow-derived mesenchymal stem cells). Conclusions: The use of ADRCs/vaPS cells can be seamlessly integrated into modern orthopedic treatment concepts, which can be understood as the optimization of a process which—albeit less efficiently—also takes place physiologically. Accordingly, this new safe and effective type of treatment is attractive in terms of holistic thinking and personalized medicine.