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

Figures

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  Fig 1. Impaired therapeutic efficacy of post-MI patient BM MNCs from the TIME and LateTIME clinical trials. Post-MI MNCs were similar to HBSS vehicle control in their lack of beneficial effect on recipient cardiac function, whereas healthy MNCs improved LVEF and minimized ventricular chamber dimensions such that ESV in only the healthy donor group was not significantly increased, with a non-significant difference between EDV from recipients of healthy cells vs. the other groups. Infarct size at 28 days post-MI showed a trend toward higher values in the post-MI donor groups and HBSS vehicle group as compared to the healthy donor group, although no significant differences were reached (P = 0.925–1.00). A representative series of stained sections cut from apex to base is presented as an example of our typical histology for these measurements; the infarct size in the ventricle shown (extent of blue scar relative to viable tissue) was 55%. Error bars = SD.

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  Fig 2. Reproducibility of TIME MNC therapeutic impairment and comparison of day 21 and 28 function. Therapeutic impairment of the TIME MNCs was also apparent in this earlier (non-blinded) pilot experiment. Moreover, EF was stable between days 21 and 28 post-recipient MI in the healthy donor MNC group, but declined during that period in the TIME MNC group. Error bars = SD.

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  Fig 3. Changes in BM MNC composition in the patients from TIME and LateTIME trials whose cells were used for implantation. MNC samples from TIME (n = 6) and LateTIME (n = 6) were quantitatively analyzed by flow cytometry and compared to healthy MNC samples (n = 22). The main findings were that TIME and LateTIME MNC samples contained fewer CD19+ cells (barely missing significance at P = 0.057 for TIME), CD31+ cells, and CD11B+ cells, and more CD3+ cells, than healthy MNC samples. There were more CD133+, CXCR4+ and CD45brightCXCR4+ cells in LateTIME MNC samples relative to healthy and TIME MNCs.

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  Fig 4. Changes in the composition of MNCs from all patients in the TIME and LateTIME clinical trials (age ≤ 55). There were fewer CD19+, CD31+, CD11B+, CD19+CXCR4+, and CD45brightCXCR4- cells; and more CD133+, CD45+CD133+, CD3+, CXCR4+, CD45brightCXCR4+, and CD34+ cells in TIME (n = 61) and LateTIME (n = 43) patients relative to age-matched healthy controls (n = 22).

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  Fig 5. Changes in miRNA profile in BM MNCs from TIME and LateTIME patients compared to those from healthy individuals. (A) Venn diagrams: (a) summarizing the differential expression of individual miRNAs in each patient group compared to the healthy group; (b) showing the number of increased miRNAs in TIME and LateTIME groups relative to the healthy group; (c) showing the number of decreased miRNAs in TIME and LateTIME groups comparable to the healthy group. (B) Changes in miRNA profile in BM MNCs from TIME and LateTIME groups compared to healthy individuals. n = 6/group; 3 females and 3 males/group. Data presented in fold-changes.