scholarly journals Impaired therapeutic efficacy of bone marrow cells from post-myocardial infarction patients in the TIME and LateTIME clinical trials

PLoS ONE ◽  
2020 ◽  
Vol 15 (8) ◽  
pp. e0237401
Author(s):  
Xiaoyin Wang ◽  
Lourdes I. Chacon ◽  
Ronak Derakhshandeh ◽  
Hilda J. Rodriguez ◽  
Daniel D. Han ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Therapeutic Efficacy ◽  
Bone Marrow Cells ◽  
Post Myocardial Infarction ◽  
Marrow Cells

scholarly journals Impaired Therapeutic Efficacy of Bone Marrow Cells from Post-Myocardial Infarction Patients in the TIME and LateTIME Clinical Trials

2019 ◽  
Author(s):  
Xiaoyin Wang ◽  
Ronak Derakhshandeh ◽  
Hilda J. Rodriguez ◽  
Daniel D. Han ◽  
Dmitry S. Kostyushev ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Therapeutic Efficacy ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Post Myocardial Infarction ◽  
Healthy Human ◽  
Human Donor ◽  
Therapeutic Benefits

AbstractImplantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

scholarly journals Influence of Cell Treatment with PDGF-BB and Reperfusion on Cardiac Persistence of Mononuclear and Mesenchymal Bone Marrow Cells after Transplantation into Acute Myocardial Infarction in Rats

2009 ◽  
Vol 18 (8) ◽  
pp. 847-853 ◽  
Author(s):  
Benjamin Krausgrill ◽  
Marius Vantler ◽  
Volker Burst ◽  
Martin Raths ◽  
Marcel Halbach ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Cell Loss ◽  
Border Zone ◽  
High Dose ◽  
Myocardial Repair ◽  
Intramyocardial Injection ◽  
Rat Hearts ◽  
Marrow Cells

Bone marrow cells are used for cell therapy after myocardial infarction (MI) with promising results. However, cardiac persistence of transplanted cells is rather low. Here, we investigated strategies to increase the survival and cardiac persistence of mononuclear (MNC) and mesenchymal (MSC) bone marrow cells transplanted into infarcted rat hearts. MNC and MSC (male Fischer 344 rats) were treated with different doses of PDGF-BB prior to intramyocardial injection into border zone of MI (syngeneic females, permanent LAD ligation) and hearts were harvested after 5 days and 3 weeks. In additional experiments, untreated MNC and MSC were injected immediately after permanent or temporary LAD ligation and hearts were harvested after 48 h, 5 days, 3 weeks, and 6 weeks. DNA of the hearts was isolated and the number of donor cells was determined by quantitative real-time PCR with Y chromosome-specific primers. There was a remarkable though not statistically significant ( p = 0.08) cell loss of ~46% between 5 days and 3 weeks in the control group, which was completely inhibited by treatment with high dose of PDGF-BB. Forty-eight hours after reperfusion only 10% of injected MSC or 1% for MNC were found in the heart, decreasing to 1% for MSC and 0.5% for MNC after 6 weeks. These numbers were lower than after permanent LAD ligation for both MNC and MSC at all time points studied. Treatment with PDGF-BB seems to prevent loss of transplanted bone marrow cells at later times presumably by inhibition of apoptosis, while reperfusion of the occluded artery enhances cell loss at early times putatively due to enhanced early wash-out. Further investigations are needed to substantially improve the persistence and survival of grafted bone marrow cells in infarcted rat hearts, in order to fully explore the therapeutic potential of this novel treatment modality for myocardial repair.

Effect of G-CSF and Intramyocardial Injection of Bone Marrow Cells on Cardiac Function in Mouse Model of Myocardial Infarction: A Word for Neo-Vasculogenesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2693-2693
Author(s):  
Larissa Verda ◽  
Kehuan Luo ◽  
Xiaoqiang Han ◽  
Andrew Wasserstrom ◽  
Jon Lomasney ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Bone Marrow Cells ◽  
Ischemia Reperfusion ◽  
Myocardial Repair ◽  
Intramyocardial Injection ◽  
Border Zones ◽  
Marrow Cells

Abstract Recent studies suggest that primitive stem cells derived from bone marrow (BM) possess greater functional plasticity that was expected previously. It has been shown that bone marrow stem cells (BMSC) promote repairing mechanisms within myocardium following ischemia/reperfusion models of myocardial infarction (MI). Although it remains unclear whether BMSC transdifferentiate into or just fuse with cardiomyocytes, hemodynamic improvement after intramyocardial BMSC injection as well as after G-CSF injection has been demonstrated. Here, we investigated the contribution of BMSC versus G-CSF administration in myocardial repair following MI. Ten weeks old C57BL/6J mice were irradiated and transplanted with green fluorescent protein (GFP) positive bone marrow cells. Three months later, these mice underwent ligation of left anterior descending branch (LAD) of coronary artery and subsequently divided into three groups. One group (n=7) received G-CSF administration at 200ug/kg for 10 consecutive days. Another group (n=9) was injected with GFP+ marrow cells directly into ischemic heart. The third group was held as control (n=7). One month after coronary ligation we found significant improvement in cardiac function determined as a cardiac output, maximum power and dP/dt, in the G-CSF group compared to control. We evaluated the phenotype of GFP+ cells within myocardium in each treatment group by 488 nm laser-scanning confocal miscroscopy (of whole heart and slides) 35 days after LAD ligation. We found no evidence of myocardial transdifferentiation or cardiomyocyte cell fusion. Instead GFP+ capillaries were present and exclusively located in infarct border zones in both the G-CSF and bone marrow implantation groups, confirmed by anti-factor VIII staining. G-CSF administration and to a lesser extent marrow injection resulted in improved post infarct cardiac function indices. This beneficial effect is not due to transdifferentiation but could be explained by marrow injected or G-CSF mobilized endothelial progenitor cells (EPC) and/or cytokine mediated neo-vasculogenesis.

Autologous Bone Marrow Cells for Treatment of Myocardial Infarction in Colombia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4171-4171
Author(s):  
Francisco Cuéllar-Ambrosi ◽  
Juán Manuel ◽  
Oscar Velásquez ◽  
Margarita Velásquez-Lopera ◽  
Claudia Navas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Heart Disease ◽  
Bone Marrow Cells ◽  
Autologous Bone Marrow ◽  
Acute Mi ◽  
Autologous Bone ◽  
Stimulating Factor ◽  
Marrow Cells

Abstract Experimental studies in animals demonstrate the ability of the bone marrow stem cells to differentiate in cardiomyocytes, vascular endothelium cells and smooth muscle cells. There is evidence that these cells can regenerate infarcted myocardium and induce myogenesis and angiogenesis. Clinical studies in humans suggest the feasibility and safety of the utilization of the stem cells to recovery the ventricular function in patients with acute myocardial infarction. We report the first experience in Colombia using autologous bone marrow cells for cardiomyoplasty in isquemic heart disease. This report shows the two months follow-up of four patients, three with acute myocardial infarction of the anterior myocardial wall and one patient with severe chronic isquemic heart disease. Extensive myocardial damage demonstrated by absence of viability in scintigraphic images and ejection fraction less than 40%. The patients received an optimum postinfarction medical treatment, successful coronary percutaneous intervention (three patients) or direct intramyocardial injection (one patient) to transfer of autologous bone marrow cells mobilised with granulocyte-colony stimulating factor during five days. Demographics and results The exercise capacity improve importantly, evidenced by increase in contractility, the six minutes test, the treadmill exercise time and the functional capacity in METS. There were not changes in the myocardial perfusion at two months follow-up, there were not complications related to the cellular transplant or the utilization of the granulocyte-colony stimulating factor. This is the first experience in Colombia with the bone marrow cells and selective intracoronary transplantation for myocardial regeneration and angiogenesis. We observed functional recovery of the left ventricle, improvement in the exercise capacity without adverse effects or complications related to the therapy. Patient # 1 2 3 4 MI= myocardial infarction, IHD= isquemic heart disease, B/A= before/after 2 months, EF= eyection fraction, ESV=end systolic volume Age/sex 51/M 23/M 59/M 53/M Diagnosis acute MI acute MI acute MI chronic IHD Diagnosis to transplant 3 weeks 2 weeks 4 weeks > 1 year CD34 dose 19.7x10(6) 16.8x10(6) 19.5x10(6) 21.7x10(6) EF% B/A 36/43 26/40 40/41 45/55 ESV (cc) B/A 80/60 116/103 65/70 101/84 METS B/A 4/14 4/17 5/12 5/14 6-min test (mts) B/A 420/540 216/462 260/450 414/727

Fractionation of mouse bone-marrow cells limits functional efficacy in non-reperfused mouse model of acute myocardial infarction

2012 ◽  
Vol 44 (8) ◽  
pp. 829-835 ◽  
Author(s):  
Juha W. Koskenvuo ◽  
Richard E. Sievers ◽  
Yan Zhang ◽  
Franca S. Angeli ◽  
Brian Lee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Mouse Model ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Mouse Bone Marrow Cells ◽  
Marrow Cells
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