Native extracellular matrix orientation determines multipotent vascular stem cell proliferation in response to cyclic uniaxial tensile strain and simulated stent indentation.

Cardiovascular disease is the leading cause of death worldwide, with multipotent vascular stem cells (MVSC) implicated in contributing to diseased vessels. MVSC are mechanosensitive cells which align perpendicular to cyclic uniaxial tensile strain. Within the blood vessel wall, collagen fibers constrain cells so that they are forced to align circumferentially, in the primary direction of tensile strain. In these experiments, MVSC were seeded onto the medial layer of decellularized porcine carotid arteries, then exposed to 10%, 1 Hz cyclic tensile strain for 10 days with the collagen fiber direction either parallel or perpendicular to the direction of strain. Cells aligned with the direction of the collagen fibers regardless of the orientation to strain. Cells aligned with the direction of strain showed an increased number of proliferative Ki67 positive cells, while those strained perpendicular to the direction of cell alignment showed no change in cell proliferation. A bioreactor system was designed to simulate the indentation of a single, wire stent strut. After 10 days of cyclic loading to 10% strain, MVSC showed regions of densely packed, highly proliferative cells. Therefore, MVSC may play a significant role in in-stent restenosis, and this proliferative response could potentially be controlled by controlling MVSC orientation relative to applied strain.

Effects of Berberine on Atherosclerosis.

Atherosclerosis is an epidemic across the globe[A1], and its morbidity and mortality remain high, involving various complications and poor prognoses. In atherosclerosis, endothelial cells (ECs) dysfunction, vascular smooth muscle cells (VSMCs) migration and proliferation, foam cell formation, and inflammatory cell recruitment contribute to disease progression. Vascular stem cells (VSCs) also play a critical role in the cardiovascular system. Important data showed that the simultaneous increase of proliferation and apoptosis of VSMCs is the main cause of graft vein stenosis, suggesting that inhibition of VSMCs proliferation and apoptosis simultaneously is an important strategy for the treatment of atherosclerotic stenosis. Complementary and alternative medicine use among patients with cardiovascular disease (CVD) is growing. Berberine is an extract of Chinese traditional herbs that is known for its antimicrobial and anti-inflammatory effects in the digestive system. Its underlying anti-CVD mechanisms are currently attracting interest, and its pharmacological actions, such as antioxidation, regulation of neurotransmitters and enzymes, and cholesterol-lowering effects, have been substantiated. Recent studying found that berberine could inhibit both the proliferation and apoptosis of VSMCs induced by mechanical stretch stress simultaneously, which suggests that berberine might be an excellent drug to treat atherosclerosis. This review will focus on the recent progress of the effect of berberine on vascular cells, especially VSMCs, to provide important data and a new perspective for the application of berberine in anti-atherosclerosis.

Lung Multipotent Stem Cells of Mesenchymal Nature: Cellular Basis, Clinical Relevance, and Implications for Stem Cell Therapy.

Significance: Tissue-resident stem cells are essential for normal organ homeostasis as well as for functional tissue regeneration after severe injury. Herein, mesenchymal stem cells, also designated as mesenchymal stromal cells (MSCs), contribute to the maintenance of organ integrity by their ability to replace dysfunctional cells or secrete cytokines locally and thus support the repair and healing processes of affected tissues. Recent Advances: Besides epithelial stem and progenitor cells, substantial evidence exists that tissue-resident multipotent stem cells of mesenchymal nature also exist in adult human lungs. These lung MSCs may function to regulate pulmonary tissue repair and/or regeneration, inflammation, fibrosis, and tumor formation. Critical Issues: Although therapeutically applied MSCs turned out to be a valuable therapeutic option for the prevention of lung diseases and/or the regeneration of diseased lung tissue, the true function of tissue-resident MSCs within the lung, and identification of their niche, which presumably dictates function, remain elusive. Future Directions: A detailed understanding of lung MSC localization (in the potential vascular stem cell niche) as well as of the signaling pathways controlling stem cell fate is prerequisite to unravel how (i) endogenous MSCs contribute to lung diseases, (ii) exogenous MSCs affect the proliferation of endogenous stem cells to repair damaged tissue, and (iii) a potential on-site manipulation of these cells directly within their endogenous niche could be used for therapeutic benefits. This review focuses on the central role of lung-resident MSCs, which are closely associated with the pulmonary vasculature, in a variety of chronic and acute lung diseases. Antioxid. Redox Signal. 35, 204-216.

Improved Isolation of Human Vascular Wall-Resident Mesenchymal Stem Cells.

Niches for tissue-resident mesenchymal stem cells (MSCs) have been identified in many adult tissues. In particular, MSCs residing in the vascular stem cell niche came into focus: the so-called vascular wall-resident MSCs (VW-MSCs) were, based upon their anatomic location, (1) distributed throughout the adult organism, and (2) supposed to be the first line cells which could be addressed in response to a pathologic trigger acting on or in close vicinity to the vascular system. Like tissue-resident MSCs in general, VW-MSC contribute to organ integrity and harbor the capacity to suppress inflammation and promote repair during normal vessel homeostasis, although resident MSCs present in the healthy situation of an individual seems not to bear sufficient for protection or repair following injury. In contrast, injury affected MSCs could contribute to disease induction and progression. A detailed understanding of the molecular repertoire as well as of the signaling pathways controlling stem cell fate of VW-MSCs is prerequisite to understand how (1) endogenous VW-MSCs contribute to normal vessel homeostasis as well as diseases that include the vascular system, (2) a potential on-site manipulation of these cells directly within their endogenous niche could be used for therapeutically benefits, and (3) isolated and therapeutically applied VW-MSCs in terms of exogenous MSCs with superior repair capabilities might be logically more efficient to address vascular diseases than MSCs derived from other tissues. This chapter describes a straightforward protocol for the improved isolation of human VW-MSCs.

Arterial Sca1+ Vascular Stem Cells Generate De Novo Smooth Muscle for Artery Repair and Regeneration.

Rapid regeneration of smooth muscle after vascular injury is essential for maintaining arterial function. The existence and putative roles of resident vascular stem cells (VSCs) in artery repair are controversial, and vessel regeneration is thought to be mediated by proliferative expansion of pre-existing smooth muscle cells (SMCs). Here, we performed cell fate mapping and single-cell RNA sequencing to identify Sca1+ VSCs in the adventitial layer of artery walls. After severe injury, Sca1+ VSCs migrate into the medial layer and generate de novo SMCs, which subsequently expand more efficiently compared with pre-existing smooth muscle. Genetic lineage tracing using dual recombinases distinguished a Sca1+PDGFRa+ VSC subpopulation that generates SMCs, and genetic ablation of Sca1+ VSCs or specific knockout of Yap1 in Sca1+ VSCs significantly impaired artery repair. These findings provide genetic evidence of a bona fide Sca1+ VSC population that produces SMCs and delineates their critical role in vessel repair.

Resident multipotent vascular stem cells exhibit amplitude dependent strain avoidance similar to that of vascular smooth muscle cells.

Atherosclerosis is one of the leading causes of mortality worldwide, and presents as a narrowing or occlusion of the arterial lumen. Interventions to re-open the arterial lumen can result in re-occlusion through intimal hyperplasia. Historically only de-differentiated vascular smooth muscle cells were thought to contribute to intimal hyperplasia. However recent significant evidence suggests that resident medial multipotent vascular stem cells (MVSC) may also play a role. We therefore investigated the strain response of MVSC since these resident cells are also subjected to strain within their native environment. Accordingly, we applied uniaxial 1 Hz cyclic uniaxial tensile strain at three amplitudes around a mean strain of 5%, (4-6%, 2-8% and 0-10%) to either rat MVSC or rat VSMC before their strain response was evaluated. While both cell types strain avoid, the strain avoidant response was greater for MVSC after 24 h, while VSMC strain avoid to a greater degree after 72 h. Additionally, both cell types increase strain avoidance as strain amplitude is increased. Moreover, MVSC and VSMC both demonstrate a strain-induced decrease in cell number, an effect more pronounced for MVSC. These experiments demonstrate for the first time the mechano-sensitivity of MVSC that may influence intimal thickening, and emphasizes the importance of strain amplitude in controlling the response of vascular cells in tissue engineering applications.

Multipotent vascular stem cells contribute to neurovascular regeneration of peripheral nerve.

BACKGROUND: Neurovascular unit restoration is crucial for nerve regeneration, especially in critical gaps of injured peripheral nerve. Multipotent vascular stem cells (MVSCs) harvested from an adult blood vessel are involved in vascular remodeling; however, the therapeutic benefit for nerve regeneration is not clear. METHODS: MVSCs were isolated from rats expressing green fluorescence protein (GFP), expanded, mixed with Matrigel matrix, and loaded into the nerve conduits. A nerve autograft or a nerve conduit (with acellular matrigel or MVSCs in matrigel) was used to bridge a transected sciatic nerve (10-mm critical gap) in rats. The functional motor recovery and cell fate in the regenerated nerve were investigated to understand the therapeutic benefit. RESULTS: MVSCs expressed markers such as Sox 17 and Sox10 and could differentiate into neural cells in vitro. One month following MVSC transplantation, the compound muscle action potential (CMAP) significantly increased as compared to the acellular group. MVSCs facilitated the recruitment of Schwann cell to regenerated axons. The transplanted cells, traced by GFP, differentiated into perineurial cells around the bundles of regenerated myelinated axons. In addition, MVSCs enhanced tight junction formation as a part of the blood-nerve barrier (BNB). Furthermore, MVSCs differentiated into perivascular cells and enhanced microvessel formation within regenerated neurovascular bundles. CONCLUSIONS: In rats with peripheral nerve injuries, the transplantation of MVSCs into the nerve conduits improved the recovery of neuromuscular function; MVSCs differentiated into perineural cells and perivascular cells and enhanced the formation of tight junctions in perineural BNB. This study demonstrates the in vivo therapeutic benefit of adult MVSCs for peripheral nerve regeneration and provides insight into the role of MVSCs in BNB regeneration.

Pericytes in the Heart.

Mural cells known as pericytes envelop the endothelial layer of microvessels throughout the body and have been described to have tissue-specific functions. Cardiac pericytes are abundantly found in the heart, but they are relatively understudied. Currently, their importance is emerging in cardiovascular homeostasis and dysfunction due to their pleiotropism. They are known to play key roles in vascular tone and vascular integrity as well as angiogenesis. However, their dysfunctional presence and/or absence is critical in the mechanisms that lead to cardiac pathologies such as myocardial infarction, fibrosis, and thrombosis. Moreover, they are targeted as a therapeutic potential due to their mesenchymal properties that could allow them to repair and regenerate a damaged heart. They are also sought after as a cell-based therapy based on their healing potential in preclinical studies of animal models of myocardial infarction. Therefore, recognizing the importance of cardiac pericytes and understanding their biology will lead to new therapeutic concepts.

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease.

Microvascular pericytes and the more recently discovered adventitial pericyte-like progenitor cells are a subpopulation of vascular stem cells closely associated with small and large blood vessels respectively. These populations of perivascular cells are remarkably abundant in the heart. Pericytes control important physiological processes such as angiogenesis, blood flow and vascular permeability. In the heart, this pleiotropic activity makes pericytes extremely interesting for applications in regenerative medicine. On the other hand, dysfunction of pericytes could participate in the pathogenesis of cardiovascular disease, such as arterial hypertension, fibro-calcific cardiovascular remodeling, myocardial edema and post-ischemic coronary no-reflow. On a therapeutic standpoint, preclinical studies in small animal models of myocardial infarction have demonstrated the healing potential of pericytes transplantation, which has been ascribed to direct vascular incorporation and paracrine pro-angiogenic and anti-apoptotic activities. These promising findings open the door to the clinical use of pericytes for the treatment of cardiovascular diseases.

Functional states of resident vascular stem cells and vascular remodeling.

Recent evidence indicates that different types of vascular stem cells (VSCs) reside within the mural layers of arteries and veins. The precise identities of these resident VSCs are still unclear; generally, postnatal vasculature contains multilineage stem cells and vascular cell lineage-specific progenitor/stem cells which may participate in both vascular repair and lesion formation. However, the underlying mechanism remains poorly understood. In this review, we summarize the potential molecular mechanisms, which may control the quiescence and activation of resident VSCs and highlight a notion that the differential states of resident VSCs are directly linked to vascular repair or lesion formation.