**5. Concluding remarks**

Angiogenesis and vasculogenesis are central events in tissue development and repair. Initially, sprouting endothelial cells form immature blood vessels that lack coverage by pericytes and other mural cells. Subsequently vascular remodelling takes place, in which association with mural cells (pericytes and SMC) stabilizes these immature vessels. Vascular remodelling is a dynamic and strictly regulated process, which is active in a variety of physiological processes, such as vessel growth, angiogenesis and wound healing. An ordered remodelling seems to be critical for proper vascular development and maintenance and is an absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. However, remodelling is also initiated during pathological processes, such as atherosclerosis, ischaemia, congenital vascular lesions, vasculotoxic therapies and tumour growth.

Organ-specific multipotent stem cell types are associated with the vessel wall, in particular within the so-called "vasculogenic zone" of the vascular adventitia. These findings together with the stem cell-supporting functions of endothelial cells suggest that the vascular wall provides niches for different somatic stem cell types within the sub-endothelial space and the vascular adventitia. It conformity with the niche function of the adventitial vasculogenic zone, the presence of Sca-1+ smooth muscle cell progenitors has been shown within this zone [131]. Furthermore, it was reported that a subset of CD34+ cells within the vascular adventitia has the capacity to differentiate into pericytes [132]. More recently, CD44(+)CD90(+)CD73(+)CD34(-)CD45(-) cells were identified within the adult human arterial adventitia, which were termed vascular wall-resident multipotent stem cells (VW-MPSCs) and were capable of differentiating into vascular SMC and pericytes under in vitro and in vivo conditions [46]. These cells reside predominantly in the vasculogenic zone of adult human blood vessels and contribute to maturation of newly formed vessels.

In general, tissue-specific stem cells differentiate mainly to the type of tissue from which they derive, indicating that there might be a certain code ("priming") within the cells determined by the tissue of origin. Furthermore, due to their anatomical localization it is believed the vessel-resident stem and progenitor cells are available as a first point of contact for the secreted factors from tumour cells (Figure 5). Without mobilization from the niche, VW-MPSCs express HOXB7, HOXC6 and HOXC8 at higher levels as compared to SMCs. These HOX genes suppress the expression of TAGLN and CNN1 in VW-MPSCs, essential factors of early SMC differentiation. This mechanism probably accounts for keeping the VW-MPSCs quiescent in the adventitial niche. In contrast, silencing of HOX genes alter the CpG methylation of TAGLN promotor resulted in increased TAGLN expression which induced VW-MPSC differentiation into SMC/pericytes [60]. Thus, as discussed here in detail, VW-MPSCs are directly involved in vascular remodelling processes as these cells represent the major source of pericytes and SMC during angiogenesis and vascular stabilization processes under physiological and pathological Vascular Wall-Resident Multipotent Stem Cells within the Process of Vascular Remodelling http://dx.doi.org/10.5772/60561 41

was associated with a commitment to a vascular smooth muscle cell lineage characterized by a strong up-regulation of calponin-1 and SM22α expression and an ability to contract the

Angiogenesis and vasculogenesis are central events in tissue development and repair. Initially, sprouting endothelial cells form immature blood vessels that lack coverage by pericytes and other mural cells. Subsequently vascular remodelling takes place, in which association with mural cells (pericytes and SMC) stabilizes these immature vessels. Vascular remodelling is a dynamic and strictly regulated process, which is active in a variety of physiological processes, such as vessel growth, angiogenesis and wound healing. An ordered remodelling seems to be critical for proper vascular development and maintenance and is an absolute prerequisite to preserve the sensitive relationship between resilience and stability of the vessel wall. However, remodelling is also initiated during pathological processes, such as atherosclerosis, ischaemia,

Organ-specific multipotent stem cell types are associated with the vessel wall, in particular within the so-called "vasculogenic zone" of the vascular adventitia. These findings together with the stem cell-supporting functions of endothelial cells suggest that the vascular wall provides niches for different somatic stem cell types within the sub-endothelial space and the vascular adventitia. It conformity with the niche function of the adventitial vasculogenic zone, the presence of Sca-1+ smooth muscle cell progenitors has been shown within this zone [131]. Furthermore, it was reported that a subset of CD34+ cells within the vascular adventitia has the capacity to differentiate into pericytes [132]. More recently, CD44(+)CD90(+)CD73(+)CD34(-)CD45(-) cells were identified within the adult human arterial adventitia, which were termed vascular wall-resident multipotent stem cells (VW-MPSCs) and were capable of differentiating into vascular SMC and pericytes under in vitro and in vivo conditions [46]. These cells reside predominantly in the vasculogenic zone of adult human

In general, tissue-specific stem cells differentiate mainly to the type of tissue from which they derive, indicating that there might be a certain code ("priming") within the cells determined by the tissue of origin. Furthermore, due to their anatomical localization it is believed the vessel-resident stem and progenitor cells are available as a first point of contact for the secreted factors from tumour cells (Figure 5). Without mobilization from the niche, VW-MPSCs express HOXB7, HOXC6 and HOXC8 at higher levels as compared to SMCs. These HOX genes suppress the expression of TAGLN and CNN1 in VW-MPSCs, essential factors of early SMC differentiation. This mechanism probably accounts for keeping the VW-MPSCs quiescent in the adventitial niche. In contrast, silencing of HOX genes alter the CpG methylation of TAGLN promotor resulted in increased TAGLN expression which induced VW-MPSC differentiation into SMC/pericytes [60]. Thus, as discussed here in detail, VW-MPSCs are directly involved in vascular remodelling processes as these cells represent the major source of pericytes and SMC during angiogenesis and vascular stabilization processes under physiological and pathological

congenital vascular lesions, vasculotoxic therapies and tumour growth.

blood vessels and contribute to maturation of newly formed vessels.

collagen matrix [130].

40 Muscle Cell and Tissue

**5. Concluding remarks**

**Figure 5. Vascular wall-resident multipotent stem cells (VW-MPSCs).** VW-MPSC mobilization and differentiation in‐ to SMC may also be induced by signals released from, e.g., tumours, inflammation and hypoxia in tissue areas around blood vessels contributing to morphogenesis of the new vessel wall. It is hypothesized that VW-MPSCs are the "firstline" cells which were mobilized from their niche towards the tumour and activated to differentiate into pericytes and SMCs, which in turn stabilize angiogenic blood vessels. The molecular analysis of these stabilizing wall cells could yield new strategies for single-target genes, which could reduce the rate of drug-resistant tumours. Without mobiliza‐ tion from the niche VW-MPSCs express specific transcription factors at high levels. These genes suppress the expres‐ sion of SMC-specific genes in VW-MPSCs. This mechanism probably accounts for keeping the VW-MPSCs quiescent in the adventitial niche. Tissue-resident MPSC and in particular VW-MPSCs, rather than circulating (BM-derived) multi‐ potent stem cells, represent the major source of pericytes and SMCs during tumour vascularization. These findings on the origin of vascular-stabilizing pericytes and their function in tumour vascularization and remodelling provide a fur‐ ther basis for the design of novel strategies to improve anti-angiogenic therapies.

conditions. Therefore, these cells may be a promising target for counteracting vascular remodelling and related anti-angiogenic drug resistance.

In future investigations, a detailed molecular analysis of vascular wall-resident multipotent stem cells and of their differentiation into pericytes in response to tumour-secreted factors may be decisive to gain a better understanding of MPSC biology and differentiation. Particularly for cancer therapy, there is an urgent need to identify signalling molecules that are selectively regulated during the process of new vessel formation and/or subsequent vascular stabilization. Targeting of such molecules might also help to minimize anti-angiogenic drug resistance due to vascular stabilization. These investigations will provide basic knowledge for the design of innovative therapeutic strategies that target those vascular remodelling processes during cancer treatment that are associated with worse prognosis, for example, the generation of drugresistant tumours.
