Timing of bone marrow cell therapy is more important than repeated injections after myocardial infarction

Division of Cardiology, Department of Medicine, University of California-San Francisco, CA 94143-0103, USA.
Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology (Impact Factor: 2). 07/2011; 20(4):204-12. DOI: 10.1016/j.carpath.2010.06.007
Source: PubMed


Bone marrow cell treatment has been proposed as a therapy for myocardial infarction, but the optimal timing and number of injections remain unknown.
Myocardial infarction was induced in mice followed by ultrasound-guided injection of mouse bone marrow cells at different time points post myocardial infarction (Days 3, 7, and 14) as monotherapy and at Days 3+7 as "double" therapy and at Days 3+7+14 as "triple" therapy. Controls received saline injections at Day 3 and Days 3+7+14. Left ventricular ejection fraction was evaluated post myocardial infarction prior to any therapy and at Day 28. Hearts were analyzed at Day 28 for infarct size and survival of donor cells.
Left ventricular ejection fraction decreased from 55.3±0.9% to 37.6±0.6% (P<.001) 2 days post myocardial infarction in all groups. Injection of bone marrow cells at Day 3 post myocardial infarction resulted in smaller infarct size (17.8±3.6% vs. 36.6±7.1%; P=.05) and improved LV function (left ventricular ejection fraction 40.3±2.0% vs. 31.1±8.3%; P<.05) compared to control. However, delayed therapy at Day 7 or 14 did not. Multiple injections of bone marrow cells, either double therapy or triple therapy, did not result in reduction in infarct size, but led to improvements in left ventricular ejection fraction at Day 28 compared to control (39.9±3.6% and 38.8±5.5% vs. 34.8±5.3%; all P<.05). The number of donor cells surviving at Day 28 did not correlate with improvement in left ventricular ejection fraction.
Injection of bone marrow cells at Day 3 reduced infarct size and improved left ventricular function. Multiple injections of bone marrow cells had no additive effect. Delaying cell therapy post myocardial infarction resulted in no functional benefit at all. These results will help inform future clinical trials.

Download full-text


Available from: Juha W Koskenvuo, Jun 04, 2014
  • Source
    • "Their results showed that the greatest therapeutic benefit was achieved following a single 3×106 cell dose injection at 6 hours post MCAo, rather than multiple lower cell infusions over multiple time points [6]. In a different study, injection of bone marrow cells at day 3 post experimental myocardial infarction in mice reduced infarct size and improved left ventricular function, while multiple injections (at day 3 and 7 or 3, 7 and 14) post myocardial infarction had no additive effect [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human umbilical tissue-derived cells (hUTC) are a promising source of cells for regenerative treatment of stroke. In this study, we tested the efficacy of hUTC in experimental stroke and whether multiple injections of hUTC provide additional therapeutic benefits as compared to a single injection. Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), and randomly selected animals were injected (i.v) with 3×10(6) hUTC or with vehicle control (at day: 1, 1&3 or 1&7 after MCAo, n = 8-9/group). A battery of functional outcome tests was performed at days 1, 7, 14, 21, 28, 35, 42, 49, 56 and 63 after MCAo. Rats were sacrificed at 63 days after MCAo and lesion volumes were measured. To investigate the underlying mechanism of hUTC treatment of stroke, Von Willebrand Factor (vWF), and Synaptophysin immunostaining were performed. All hUTC treated groups, single or multiple injections, had better functional recovery compared to control (p<0.01). There was no statistically significant difference between a single and multiple injections of hUTC (p = 0.23) or between different multiple injections groups (p>0.07) in functional outcome. All hUTC treatment groups showed significant increases in Synaptophysin, vascular density and perimeter compared to the control group (p<0.05). There was no statistically significant difference between a single and multiple injections of hUTC or between the two groups of multiple injections in all immunohistochemical measurements (p>0.1). hUTC treatment significantly improves long term functional outcome after stroke and promotes vascular density and synaptic plasticity. At the proscribed doses, multiple injections of hUTC were not superior to single injection therapy in both functional outcome and histological assessments.
    Full-text · Article · Jan 2013 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this article is to present an analysis of current knowledge and understanding of the role of stem cells in myocardial biology and myocardial repair following injury. This rapidly evolving field has assumed relevance for the understanding, diagnosis, and treatment of heart failure.
    No preview · Article · Sep 2011 · Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.
    Full-text · Article · Sep 2011 · Science translational medicine
Show more