Multipotent adult progenitor cells sustain function of ischemic limbs in mice
Xabier L. Aranguren, … , Catherine M. Verfaillie, Aernout Luttun
Xabier L. Aranguren, … , Catherine M. Verfaillie, Aernout Luttun
Published February 1, 2008; First published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):505-514. https://doi.org/10.1172/JCI31153.
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Research Article Vascular biology

Multipotent adult progenitor cells sustain function of ischemic limbs in mice

Abstract

Despite progress in cardiovascular research, a cure for peripheral vascular disease has not been found. We compared the vascularization and tissue regeneration potential of murine and human undifferentiated multipotent adult progenitor cells (mMAPC-U and hMAPC-U), murine MAPC-derived vascular progenitors (mMAPC-VP), and unselected murine BM cells (mBMCs) in mice with moderate limb ischemia, reminiscent of intermittent claudication in human patients. mMAPC-U durably restored blood flow and muscle function and stimulated muscle regeneration, by direct and trophic contribution to vascular and skeletal muscle growth. This was in contrast to mBMCs and mMAPC-VP, which did not affect muscle regeneration and provided only limited and transient improvement. Moreover, mBMCs participated in a sustained inflammatory response in the lower limb, associated with progressive deterioration in muscle function. Importantly, mMAPC-U and hMAPC-U also remedied vascular and muscular deficiency in severe limb ischemia, representative of critical limb ischemia in humans. Thus, unlike BMCs or vascular-committed progenitors, undifferentiated multipotent adult progenitor cells offer the potential to durably repair ischemic damage in peripheral vascular disease patients.

Authors

Xabier L. Aranguren, Jonathan D. McCue, Benoit Hendrickx, Xiao-Hong Zhu, Fei Du, Eleanor Chen, Beatriz Pelacho, Ivan Peñuelas, Gloria Abizanda, Maialen Uriz, Sarah A. Frommer, Jeffrey J. Ross, Betsy A. Schroeder, Meredith S. Seaborn, Joshua R. Adney, Julianna Hagenbrock, Nathan H. Harris, Yi Zhang, Xiaoliang Zhang, Molly H. Nelson-Holte, Yuehua Jiang, An D. Billiau, Wei Chen, Felipe Prósper, Catherine M. Verfaillie, Aernout Luttun

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Figure 1

mMAPC-U and hMAPC-U engraftment and differentiation.

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mMAPC-U and hMAPC-U engraftment and differentiation. (A–F) At 14 days, c...
(A–F) At 14 days, cell patches (dotted lines in A and B) were found by in vivo (A) or ex vivo (B) imaging, GFP fluorescence (C), and anti-GFP staining in cross sections (D). Note positioning of the patches near α-SMA+ (red in E) vessels and the surrounding CD45+ (red in F) clusters. (G–I) At 14 days, confocal imaging revealed some GFP+ cells coexpressing CD31 or α-SMA (arrowheads in G and H, respectively). A limited number of regenerating SkMBs were GFP+ (thus donor derived; revealed by anti-GFP staining; I). (J–L) At 5 weeks, mMAPC-U persisted (shown by in vivo imaging, J; and anti-GFP staining, K and L). Note that donor-derived regenerating fibers (GFP+ cells in K) were still apparent and that cell number was less than it was at 14 days (compare D and L). (M–P) At 30 days, hMAPC-U stably engrafted (revealed by large human vimentin+ [green] cell patches intercalated between muscle fibers [M and N] and as scattered cells around vessels [P]). Cells were detected in the endothelial layer of vessels by a human-specific anti-CD31 antibody (green in O), indicating EC differentiation, and in some cells the human vimentin signal (green) colocalized (yellow; white arrowheads) with α-SMA (red), indicating their SMC identity in P. Images in A, C, D, E, G–J, L, M, O, and P are from adductor; images in B, F, I, and K from gastrocnemius and N from quadriceps muscle. DAPI was used as nuclear counterstain in C and E and M–O and Topro (Molecular Probes) in H and P. Scale bars: 50 μm (G–I, K), 100 μm (C, D, F, L, M, O, and P), 200 μm (E and N), and 500 μm (A, B, and J).