- 作者：Udi Sarig ; PhD<sup>asup><sup> ; sup><sup>1sup> ; Hadar Sarig ; PhD<sup>asup><sup> ; sup><sup>1sup> ; Elio de-Berardinis ; MSc<sup>asup> ; Su-Yin Chaw ; MSc<sup>asup> ; Evelyne B.V. Nguyen ; PhD<sup>asup> ; Vaibavi S. Ramanujam ; MSc<sup>bsup> ; Vu D. Thang ; MD<sup>bsup> ; Muthafar Al-Haddawi ; DVSc ; PhD ; Dip. ACVP<sup>csup> ; Susan Liao ; PhD<sup>asup> ; Dror Seliktar ; PhD<sup>bsup><sup> ; sup><sup>dsup> ; Theodoros Kofidis ; MD ; PhD<sup>bsup> ; Freddy Y.C. Boey ; PhD<sup>asup> ; Subbu S. Venkatraman ; PhD<sup>asup><sup> ; sup><sup>assubbu@ntu.edu.sg" class="auth_mail" title="E-mail the corresponding authorsup> ; Marcelle Machluf ; PhD<sup>asup><sup> ; sup><sup>esup><sup> ; sup><sup>machlufm@tx.technion.ac.il" class="auth_mail" title="E-mail the corresponding authorsup>
- 关键词：Myocardial infarction ; Heart regeneration ; Extracellular matrix ; Tissue engineering ; Cardiac progenitors ; Bioactive patch
- 刊名：Acta Biomaterialia
- 出版年：2016
- 出版时间：15 October 2016
- 年：2016
- 卷：44
- 期：Complete
- 页码：209-220
- 全文大小：4886 K
sSec_2">Background
sp0015">pcECM is a key natural biomaterial that can affect cardiac regeneration following myocardial infarction (MI), through mechanisms, which are still not clearly understood.
sSec_3">Methods
sp0020">Wistar rats underwent MI and received pcECM patch (pcECM-P) treatment in either acute or chronic inflammatory phases. Treated, sham operated (no MI), and control (MI without treatment) animals, were compared through echocardiography, hemodynamics, pathological evaluation and analyses of various mRNA and protein level markers.
sSec_4">Results
sp0025">Our results show that in both acute and long-term chronic MI models, pcECM promotes significant cardiac function improvement, which is correlated to progenitor (GATA4<sup>+sup>, c-kit<sup>+sup>) and myocyte (MYLC<sup>+sup>, TRPI<sup>+sup>) recruitment. Interestingly, recruited progenitors, isolated using laser capture microdissection (LCM), expressed both early and late cardiomyocyte (CM) differentiation markers, suggesting differentiation towards the CM lineage. Recruited CM-like cells organized in a partially striated and immature muscle fiber arrangement that presented connexin43 —a crucial mediator of cardiac electrical conductivity. Concomitantly, pcECM was rapidly vascularized, and induced a constructive remodeling process as indicated by increased M2/M1 macrophage phenotypic ratio and pathological evaluation.
sSec_5">Conclusions
sp0030">Acellular pcECM patch implants alone, i.e., without added biologics, are bioactive, and exert potent efficacy, stimulating biological regenerative processes that cooperatively lead to a cardiac progenitor-based restoration of function, even after scar tissue had already formed.
sSec_6">Statement of Significance
sp0035">MI (‘heart attack’) remains the leading cause of heart failure and death in developed-countries. Restoration of cardiac function requires active turnover of damaged heart contracting cells (CM), however, CM endogenous regeneration is not efficient and is a matter of controversy. We show that a bioactive biomaterial alone—decellularized heart tissue (pcECM)—without added cells or growth factors, can elicit a complex regenerative response even after irreversible scarring. The pcECM patch induces macrophage polarization towards constructive remodeling and cardiomyocyte progenitor cell (GATA4<sup>+sup>, c-kit<sup>+sup>) recruitment (evidenced at both mRNA and protein levels) resulting in de novo immature striated-like muscle patterns (MLC<sup>+sup>, TrpI<sup>+sup>, connexin43<sup>+sup>). We, therefore, suggest this bioactive pcECM can model cardiac regeneration, and serve as a candidate for fast-track clinical application.