Targeting pericytes for neurovascular regeneration

Abstract

Pericytes, as a key cellular part of the blood-brain barrier, play an important role in the maintenance of brain neurovascular unit. These cells participate in brain homeostasis by regulating vascular development and integrity mainly through secreting various factors. Pericytes per se show different restorative properties after blood-brain barrier injury. Upon the occurrence of brain acute and chronic diseases, pericytes provoke immune cells to regulate neuro-inflammatory conditions. Loss of pericytes in distinct neurologic disorders intensifies blood-brain barrier permeability and leads to vascular dementia. The therapeutic potential of pericytes is originated from the unique morphological shape, location, and their ability in providing vast paracrine and juxtacrine interactions. A subset of pericytes possesses multipotentiality and exhibit trans-differentiation capacity in the context of damaged tissue. This review article aimed to highlight the critical role of pericytes in restoration of the blood-brain barrier after injury by focusing on the dynamics of pericytes and cross-talk with other cell types.

Keywords: Angiogenesis potential; Blood-brain barrier restoration; Pericytes.

Fig. 1

Pericytes contribute in homeostasis of the BBB through different mechanisms. TGF-β signaling inside pericytes supports the BBB integrity by enhancing fibronectin production, basal membrane formation and stimulating tight junctions expression. TGF-β signaling also participates in capillary-like structures formation. Along with TGF-β signaling, pericytes derived Ang-1 enhances occludin up-regulation inside ECs which stabilize BBB integrity. Mutually, ECs support adjacent pericytes by improving pericyte-EC integration by up-regulating N-cadherin and the prevention of pericytes migration. Two mechanisms have been suggested for ECs supporting role. First, TGF-β and BMP signaling pathways play enhancing role on N-cadherin up-regulation inside ECs through Smad4. The second mechanism is related to the stimulatory effect of VEGF in the expression of DLL4 inside ECs and attaching to receptor Notch3 on pericytes surface, triggering Notch signaling, N-cadherin up-regulation inside pericytes. Various mechanisms have been identified for the induction of pericytes proliferation and migration. During hyperglycemia or hypoxia, an elevated Ang-2 level activates cognate receptor Tie-2 which induces pericytes migratory activity by detaching cells from the ECM. The inductive mechanism for Ang-2 elevation in hypoxia occurs via pericytes HIF-1α and subsequent VEGF signaling. Also, the promotion of HIF-1α, VEGF, and Nox4 signaling after hypoxia enhances pericytes proliferative activity. In response to hypoxia, pericytes support neuronal survival with astrocytes collaboration. After hypoxia, pericytes NT-3 releasing activates astrocytes TrkC receptors in which upregulates NGF through ERK1/2 signaling pathway. Pericytes plays a major role in diabetic pathology and other hyperglycemic conditions. In these circumstances, pericytes respond to accumulated AGEs through various mechanisms. ANG-2-related activation of ANG type 1 receptor inside retina and AGEs stimulated TGF-β autocrine signaling inside pericytes, leading to basal membrane hypertrophy through increased production of fibronectin. The postulated mechanism for diabetic retinopathy via AGEs receptors occurs by activating downstream Src-Erk1/2-FAK-1-Paxillin signaling pathway which leads to diabetic retinopathy and pericytes migration. Also, HIV and ANG-2 cause pericytes migration and diabetic retinopathy through PDGF-BB autocrine signaling. Inside ECs claudin 5 down-regulation via VEGF and MMP-2 elevation leads to BBB disruption. Different types of CNS diseases such as ischemic stroke, intracerebral hemorrhage, Alzheimer’s disease, and Parkinson’s disease weaken BBB integrity through activating pericytes. By thrombin elevation in CNS diseases, PAR1 activation results in MMP-9 secretion and subsequent ECM degradation through downstream PKCδ-ERK1/2 and PKCθ-Akt signaling pathways. In addition, there are other mechanisms for MMP-9 release and ECM degradation after ischemic stroke related to increased TNF-α content and up-regulation MMP-9 inside pericytes through MAPK and PI3K/Akt signaling pathways. VEGF production inside pericytes happens and subsequent BBB disruption occurs through decreasing claudin 5 expression. In spite of these disruptive mechanisms of pericytes in response to ischemic stroke, pericytes behavior complexity stigmatizes its role by exerting CNS homeostasis, neuroprotective and angiogenic activity after ischemic stroke. The hypoxia-induced FGFR1 up-regulation and tissue acidification promotes bFGF autocrine signaling inside pericytes following ischemic stroke which intensifies PDGFRB up-regulation. PDGFRB signaling activation supports CNS homeostasis, neuroprotection, and angiogenesis through releasing growth factors microvesicles and generating fibrotic scar. TSP1 reinforces PDGFRB signaling aiming to pericytes proliferation and migration

Fig. 2

Under pathologic circumstances, pericytes present stemness or trans-differentiation potential. Brain injury induces pericytes to leave capillary and achieve microglial phenotype while pericyte marker expression retains. After ischemic stroke, the suppression of the pericytes aPKC-CBP signaling pathway contributes in reemergence of induced neural precursors markers 3 days post-stroke. However, iSCs generation in ischemic regions pericytes is plausible by co-expressing MSCs, Neural stem/progenitor cells, and vascular lineage markers along with pericytes markers. Utilization of neural- or endothelial-conditioned medium on iPCs culture in vitro leads to neural or vascular lineage generation