Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells
Jeffrey J. Ross, … , Robert T. Tranquillo, Catherine M. Verfaillie
Jeffrey J. Ross, … , Robert T. Tranquillo, Catherine M. Verfaillie
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3139-3149. https://doi.org/10.1172/JCI28184.
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Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells

Abstract

Smooth muscle formation and function are critical in development and postnatal life. Hence, studies aimed at better understanding SMC differentiation are of great importance. Here, we report that multipotent adult progenitor cells (MAPCs) isolated from rat, murine, porcine, and human bone marrow demonstrate the potential to differentiate into cells with an SMC-like phenotype and function. TGF-β1 alone or combined with PDGF-BB in serum-free medium induces a temporally correct expression of transcripts and proteins consistent with smooth muscle development. Furthermore, SMCs derived from MAPCs (MAPC-SMCs) demonstrated functional L-type calcium channels. MAPC-SMCs entrapped in fibrin vascular molds became circumferentially aligned and generated force in response to KCl, the L-type channel opener FPL64176, or the SMC agonists 5-HT and ET-1, and exhibited complete relaxation in response to the Rho-kinase inhibitor Y-27632. Cyclic distention (5% circumferential strain) for 3 weeks increased responses by 2- to 3-fold, consistent with what occurred in neonatal SMCs. These results provide evidence that MAPC-SMCs are phenotypically and functionally similar to neonatal SMCs and that the in vitro MAPC-SMC differentiation system may be an ideal model for the study of SMC development. Moreover, MAPC-SMCs may lend themselves to tissue engineering applications.

Authors

Jeffrey J. Ross, Zhigang Hong, Ben Willenbring, Lepeng Zeng, Brett Isenberg, Eu Han Lee, Morayma Reyes, Susan A. Keirstead, E. Kenneth Weir, Robert T. Tranquillo, Catherine M. Verfaillie

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Figure 8

Functional assessment of CD (5% circumferential strain) on week 5 fibrin ring constructs of F-MAPC-SMCs or rat neonatal SMCs.

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Functional assessment of CD (5% circumferential strain) on week 5 fibrin...
Contractile responses reported as milligrams in samples exposed to CD or no strain (static). Traces of induction by KCl (A) or ET-1 (B) produced greater force in CD-exposed F-MAPC-SMCs compared with static samples. (C) Vasodilation during KCl contraction was achieved by the Rho-kinase inhibitor Y-27632. Acetylcholine (ACh) had no effect. Five percent strain increased the level of contractility of primary cultured neoRAOSMCs (D) and F-MAPC-SMCs (E) to KCL, 5-HT, and FPL64176, while responses to ET1 were decreased in RAOSMCs following CD (*P < 0.05; n = 3–6). Remodeling levels as determined by total collagen (F) or elastin (G) production were unaffected by CD in F-MAPC-SMC constructs, whereas constructs in which endothelial cells were incorporated did not contain any detectable elastin or collagen (P < 0.01; n = 4–5). (H) Expression of Cav1.2, collagen type III, and tropoelastin was increased in CD compared with static samples after 5 weeks (n = 4–5).