The stem cell shell game. Focus on "The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture"

Natalia Landázuri1 and W. Robert Taylor1,2

1Division of Cardiology, Department of Medicine, Emory University School of Medicine, and 2Veterans Affairs Medical Center, Atlanta, Georgia

STEM CELLS, initially thought to exist exclusively during embryonic stages of development, have now been shown to remain present in the adult body. They represent a potential means for lifelong repair and regeneration of injured tissues. The possibility of exploiting this regenerative potential is extremely attractive and may lead to the development of novel therapies.

One of the critical areas from a pathological standpoint that could significantly benefit from directed differentiation of adult stem cells or more committed progenitor cells is vascular medicine. The most obvious of the possible therapeutic uses of progenitor cells is the revascularization of ischemic or infarcted tissues. Alternatively, pathological vascularization in tumors could be inhibited as a result of a better understanding of how progenitor cells contribute to angiogenesis.

Unfortunately, to date, vascular progenitor cells have only been partially characterized, and their location and functionality within the body remains a topic of debate. Vascular progenitor cells have been described by different research groups in the bone marrow, peripheral blood, and solid tissues. However, the true identity of these cells, their origin, as well as their ability to incorporate into adult vascular tissue, is controversial. Bone marrow-derived cells have been reported to migrate to areas of ischemia and incorporate into the vasculature, but the number of cells found to differentiate into a vascular phenotype varies considerably in the literature (2, 4, 12). Moreover, some studies have failed to detect bone marrow-derived cells within the vasculature, despite the fact that they accumulate in areas of ischemia (8, 14). Cells that migrate to areas of ischemia seem to be mostly leukocytes, especially monocyte/macrophages, and assist vascularization in a paracrine manner, by secreting angiogenic growth factors and cytokines. The origin of these monocyte/macrophages is also uncertain, as some data demonstrate that macrophages proliferate in the resident tissue during the acute phase of ischemia and do not migrate from the bone marrow or the peripheral circulation (7). Finally, there is also evidence that immature vascular cells reside in peripheral tissues. For example, skeletal muscle contains various populations of vascular progenitors (3, 9), but it is not clear whether skeletal muscle cells and vascular cells share a common progenitor or mixed populations of progenitors are present within the skeletal muscle.

In the present article in focus, Howson et al. (Ref. 2a; see p. C1396 in this issue) examine the possibility that progenitor cells are present within the aorta. They have identified a population of nonadherent mesenchymal cells from the postnatal rat aorta. These cells proliferate, form clusters in suspension, and remain undifferentiated when cultured in the absence of serum. Interestingly, when cultured in the presence of serum, the cells attach and terminally differentiate into pericytes.

The authors (2a) provide strong evidence that these differentiated cells are pericytes, through analysis of their phenotype, morphology, and functionality. Differentiated cells express markers typical of mural cells that are not expressed by the progenitor cells. When cultured in a three-dimensional collagen gel and treated with growth factors, the progenitor cells migrate and adopt a dendritic morphology characteristic of pericytes. When cultured with angiogenic outgrowths of rat aorta or with rat aortic endothelial cells, the progenitor cells generate a coating of mural cells surrounding endothelial cells.

The finding that the aorta contains vascular progenitor cells is in line with the finding that the aorta supports the embryonic emergence of hematopoietic and vascular progenitor cells (11) and raises the possibility that progenitor cells are present within the vasculature throughout postnatal development. On the other hand, it remains to be determined whether pericyte progenitor cells are present throughout the vasculature or reside only in the aorta. The former scenario would permit an in situ differentiation of progenitor cells during repair and regeneration. The latter scenario would require cells to be transported via the circulation to areas of neovascularization. To reconcile the results from Howson et al. (2a) and previous studies showing that progenitor cells reside in the bone marrow, in the peripheral vasculature, and in other tissues, we could speculate that progenitor cells are transported from the bone marrow or from peripheral tissues, through the circulation, to other tissues. Once engrafted in a tissue, they can remain latent until stimulated to proliferate and differentiate. This possibility is consistent with previous studies showing that bone marrow-derived progenitor cells engraft into the brain and skeletal muscle (6, 9).

Howson et al. (2a) describe a method to isolate and culture populations of primitive mural cells ex vivo. These cells can proliferate and remain undifferentiated for several months. This method opens the door to potential therapies using a small number of autologous progenitor cells. Cells isolated from patients could be stimulated to proliferate ex vivo and then be delivered to areas of vascularization. Moreover, ex vivo cultures can be used to characterize in detail the phenotype of mural progenitor cells and, in turn, to facilitate recognition and isolation of these cells from other sites of the body. In fact, it has been difficult to verify the location and identity of vascular progenitor cells because they are not well characterized and cannot be distinguished from other lineages of immature cells, such as hematopoietic stem cells (5, 10, 13).

Additionally, in vitro cultures of progenitor cells will make it simpler to characterize the series of events that take place during differentiation, that is, how cells respond to the microenvironment, how maturation occurs within the cell, and what are the major paracrine and autocrine factors that stimulate angiogenesis. Howson et al. (2a) induced differentiation of pericytes by culturing progenitor cells in the presence of serum but did not examine what key components of serum were necessary for cell maturation. Once identified, these components could be used to alter the differentiation process for therapeutic purposes. For example, they could be delivered in vivo to activate progenitor cells and promote vascularization or be inhibited to disrupt vascularization under pathological conditions. Alternatively, they could be delivered by genetically modifying the progenitor cells and inducing them to express a given growth factor, as has been proposed in previous studies (1, 4).

Finally, the possibility of isolating and culturing populations of mural progenitor cells can greatly contribute to the field of vascular tissue engineering. Howson et al. (2a) show that progenitor cells cultured in three-dimensional collagen gel matrix and in the presence of vascular outgrowths migrate to areas of active vascularization. Therefore, we could envision tissue engineering constructs that provide a scaffold suitable for incorporation of these and other vascular progenitors. Such constructs would be biocompatible and closely mimic the morphological, structural, and functional structure of blood vessels.

The study by Howson et al. (2a) provides strong evidence that functional vascular progenitor cells reside in the postnatal aorta. This important finding recapitulates a model that exists in other organ systems and challenges our concepts of not only the location but the types of vascular progenitor cells that are present in the adult vasculature.


    FOOTNOTES
 

Address for reprint requests and other correspondence: W. R. Taylor, Division of Cardiology, Dept. of Medicine, Emory Univ. School of Medicine, Atlanta, GA 30322 (e-mail: wtaylor{at}emory.edu)


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