The Time Window for Therapy with Peptide Nanofibers Combined with Autologous Bone Marrow Cells in Pigs after Acute Myocardial Infarction
March
The Time Window for Therapy with Peptide Nanofibers Combined with Autologous Bone Marrow Cells in Pigs after Acute Myocardial Infarction
Ming-Yao Chang 0 1
Chih-Han Chang 0 1
Chien-Hsi Chen 0 1
Bill Cheng 0 1
Yi-Dong Lin 0 1
Chwan- Yau Luo 0 1
Hua-Lin Wu 0 1
Yu-Jen Yang 0 1
Jyh-Hong Chen 0 1
Patrick C. H. Hsieh 0 1
0 1 Department of Biomedical Engineering, National Cheng Kung University , Tainan , Taiwan , 2 Institute of Biomedical Sciences , Academia Sinica, Taipei, Taiwan , 3 Department of Surgery, National Cheng Kung University & Hospital , Tainan , Taiwan , 4 Department of Biochemistry and Molecular Biology, National Cheng Kung University , Tainan , Taiwan , 5 Department of Internal Medicine, National Cheng Kung University & Hospital , Tainan , Taiwan
1 Academic Editor: Guo-Chang Fan, University of Cincinnati, College of Medicine, UNITED STATES
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Funding: This work was supported by the National
Research Program for Biopharmaceuticals
(DOH101TD-PB-111-TM027 and
DOH101-TD-PB-111TM028), the National Science Council
(NSC1012325-B-006-013), the National Health Research
Institutes (NHRI-EX101-10026SI), the Academia
Sinica Translational Medicine Program and Celgene
Cellular Therapeutics and Meridigen Biotech Co. The
funders had no role in study design, data collection
We previously showed that injection of peptide nanofibers (NF) combined with autologous
bone marrow mononuclear cells (MNC) immediately after coronary artery ligation improves
cardiac performance in pigs. To evaluate the clinical feasibility, this study was performed to
determine the therapeutic time window for NF/MNC therapy in acute myocardial infarction
(MI).
A total of 45 adult minipigs were randomly grouped into 7 groups: sham or MI plus treatment
with NS (normal saline), or NF or MNC alone at 1 day (1D) post-MI, or NF/MNC at 1, 4, or 7
days post-MI (N 6). Cardiac function was assessed by echocardiography and ventricular
catheterization. Compared with the NS control, pigs treated with NF/MNC at 1 day post-MI
(NF/MC-1D) had the greatest improvement in left ventricle ejection fraction (LVEF; 55.11.6%;
P<0.01 vs. NS) 2 months after MI. In contrast, pigs treated with either NF/MNC-4D or NF/
MNC-7D showed 48.90.8% (P<0.05 vs. NS) and 43.52.3% (n.s. vs. NS) improvements,
respectively. The +dP/dt and -dP/dt, infarct size and interstitial collagen content were also
improved in the NF/MNC-1D and -4D groups but not in the -7D group. Mechanistically, MNC
quality and the states of systemic inflammation and damaged heart tissue influence the
therapeutic efficiency of NF/MNC therapy, as revealed by another independent study using 16 pigs.
Injection of NF/MNC at 1 or 4 days, but not at 7 days post-MI, improves cardiac performance
and prevents ventricular remodeling, confirming the importance of early intervention when
using this therapy for acute MI.
The limited regenerative ability of mammalian cardiomyocytes renders them vulnerable to
myocardial infarction (MI), which results in irreversible cardiomyocyte death. This leads to
cardiac dysfunction and, ultimately, heart failure. Recently, stem cell therapy has shown
promising outcomes and has opened a new window for cardiac reparative and regenerative medicine
[1]. Among the cell types used for cardiac cell therapy, the bone marrow cell (BMC) is of
particular interest because of the availability of abundant autologous BMCs for transplantation
[24]. However, although BMC therapy can achieve a certain level of cardiac protection, there
are still many obstacles to the successful treatment of MI by this approach. For example, the
loss of intramyocardially injected cells is inevitable because the heart is a constantly contracting
organ. Previous studies have demonstrated that only 1.3~2.6% of the administered cells were
detected 1.5 hours after the injection [5]. It is now widely accepted that the effectiveness of cell
therapy in improving cardiac function heavily depends on the cell retention numbers [6].
Another important issue is the timing of cell delivery. Specifically, even though BMC
transplantation has been shown to be safe [7], the effective therapeutic time window of this
treatment has rarely been explored [8,9]. Although some clinical data show improved left ventricle
ejection fraction (LVEF), scar size, and ventricle volume in patients injected with BMCs within
7 days of MI [10], other studies indicate that the delivery of bone marrow mononuclear cells
(MNCs) in early or later time points after acute MI has no significant benefits on cardiac
function [1113].
We have used a hydrogel-based tissue engineering approach to promote cell retention and
recruitment for post-MI cardiac repair in rats and pigs [1416]. In a recent pig study, we
reported that injecting self-assembling peptide nanofibers (NF) combined with autologous MNC
increases cell retention/survival by approximately 8-fold at 1 month post-MI, improving
cardiac performance and preventing remodeling [17]. To further investigate t (...truncated)