Bone Marrow-Derived Progenitor Cells Augment Venous Remodeling in a Mouse Dorsal Skinfold Chamber Model

Megan E Doyle,Thomas C Skalak,Jeffrey P Perley,Wei-Chun Chin

doi:10.1371/journal.pone.0032815

Abstract

The delivery of bone marrow-derived cells (BMDCs) has been widely used to stimulate angiogenesis and arteriogenesis. We identified a progenitor-enriched subpopulation of BMDCs that is able to augment venular remodeling, a generally unexplored area in microvascular research. Two populations of BMDCs, whole bone marrow (WBM) and Lin−/Sca-1+ progenitor cells, were encapsulated in sodium alginate and delivered to a mouse dorsal skinfold chamber model. Upon observation that encapsulated Sca-1+ progenitor cells enhance venular remodeling, the cells and tissue were analyzed on structural and molecular levels. Venule walls were thickened and contained more nuclei after Sca-1+ progenitor cell delivery. In addition, progenitors expressed mRNA transcript levels of chemokine (C-X-C motif) ligand 2 (CXCL2) and interferon gamma (IFNγ) that are over 5-fold higher compared to WBM. Tissues that received progenitors expressed significantly higher protein levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and platelet derived growth factor-BB (PDGF-BB) compared to tissues that received an alginate control construct. Nine days following cell delivery, tissue from progenitor recipients contained 39% more CD45+ leukocytes, suggesting that these cells may enhance venular remodeling through the modulation of the local immune environment. Results show that different BMDC populations elicit different microvascular responses. In this model, Sca-1+ progenitor cell-derived CXCL2 and IFNγ may mediate venule enlargement via modulation of the local inflammatory environment.

Highlights

Microvascular adaptations occur through the processes of angiogenesis, arteriogenesis, and venule remodeling in response to both physiological and pathological stimuli
Sca-1+ Progenitors Cells Augment Venular Remodeling The mouse dorsal skinfold window chamber model was used to evaluate the impact of delivered bone marrow-derived cells (BMDCs) on microvascular remodeling (Figure 1)
BMDCs had a significant impact on venular remodeling (Figure 2C), Sca-1+ progenitor cells on the larger venules in the tissue (Figure 2D)

Summary

Introduction

Microvascular adaptations occur through the processes of angiogenesis, arteriogenesis, and venule remodeling in response to both physiological and pathological stimuli. Bone marrow-derived cells (BMDCs), is actively investigated as a means to stimulate the growth of new vasculature or enlargement of pre-existing vessels [1,2]. The known effects of BMDCs on angiogenesis and arteriogenesis in the microcirculation supports the use of these cells for therapeutic benefit [1,3,4,5]. The impact of these cells on the venular side of these microvascular networks, is less established. Exogenous BMDCs are most often delivered to tissue via local cell injection, but some studies have used implantable matrices to deliver these cells in an effort to improve cell retention in the tissue [17,18]

Methods

Results

Conclusion