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In larger blood vessels such as arteries, EC are covered by the tunica media, a contractile structure composed of several layers of SMCs, which is surrounded by a connective tissue termed the adventitia. The adventitia is in direct contact with the surrounding tissue and contains a mesenchymal subset termed adventitial fibroblasts expressing CD34, Sca-1 and PDGFRα, small blood vessels (vasa vasorum), lymphatic vessels, nerves, and immune cells embedded within a collagenous matrix. In the past few years, a subset of mesenchymal progenitors called mesenchymal stromal cells/mesenchymal stem cells (MSCs) have been identified in the perivascular space of several organs. Due to their proximity to blood vessels and expression of common markers such as PDGFRα, PDGFRβ or CD34, these cells were suggested to be similar or related to pericytes and adventitial fibroblasts [3, 4, 5, 6]. Other commonly used markers for MSCs in mice include CD105, Sca-1, CD44, CD29 or CD90. MSC were first identified in the bone marrow (BM) as multipotent, self-renewing mesenchymal progenitors that have the capability, in single-cell assays, of generating bone, cartilage, adipocytes and hematopoiesis-supporting stromal cells. The gene signature and differentiation potential of MSCs from other organs is still debated and varies according to the tissue of origin [7,8]. When isolated from organs (in particular from the adipose tissue where they are abundant), expanded in vitro for several generations and re-injected, MSCs have been shown to have a beneficial effect in several pathologies affecting the heart, bone, lung and skin [6,9, 10, 11]. As integral constituents of the blood vessels wall, pericytes and adventitial fibroblasts are essential regulators of vascular development, maturation and function (reviewed in Refs. [12,13]). In the CNS, pericytes regulate the cerebral blood flow and maintain the blood-brain barrier [14, 15, 16]. Accordingly, pericytes loss is involved in the microvascular dysfunction characteristic of several inflammatory/fibrotic diseases, neurodegenerative diseases and cancer [17,18]. Here we review recent evidence that, in addition to their vascular role, pericytes and adventitial fibroblasts are essential regulators of inflammation and a critical component of tissue homeostasis. These novel data suggest that mesenchymal cells localized within or around blood vessels organize tissue responses by distinct mechanisms, including recruitment, activation and/or modulation of immune cells such as neutrophils, monocytes/macrophages and type 2 innate lymphoid cells (ILC2s), as well as differentiation into specialized mesenchymal subsets such as lymphoid stromal cells or myofibroblasts which have a central role in immunity and repair, respectively (Figure 2).

Proposed functions for mesenchymal cells of the perivascular niche. In addition to their vascular role, pericytes and adventitial cells regulate inflammation and tissue homeostasis/repair by regulating recruitment and/or activity of immune cells, in particular myeloid cells and innate lymphoid cells. Furthermore, specific subsets of perivascular mesenchymal cells can act as progenitors for matrix-producing fibroblasts (following tissue injury) or lymphoid stromal cells such as TRCs, FDC, MRCs in lymphoid organs development. MSC: mesenchymal stromal cells; TRC: T-zone reticular cells; FDC: Follicular dendritic cells; MRC: marginal reticular cells.