Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells.
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-beta1 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.
Ross
Jeffrey J
JJ
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA.
Hong
Zhigang
Z
Willenbring
Ben
B
Zeng
Lepeng
L
Isenberg
Brett
B
Lee
Eu Han
EH
Reyes
Morayma
M
Keirstead
Susan A
SA
Weir
E Kenneth
EK
Tranquillo
Robert T
RT
Verfaillie
Catherine M
CM
D000818:Animals; D000831:Animals, Newborn; D000077214:Becaplermin; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D005337:Fibrin / Q000378:metabolism / Q000502:physiology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C071658:FPL 64176; D000077214:Becaplermin; D005337:Fibrin