Over the past 10 years, several studies have been carried out to determine whether the infusion of peripheral blood (PBSC) or bone marrow-derived cell products (mononuclear, CD34, CD133 or ALDH cells) may improve cardiac function, after myocardial infarction (MI). The hypothesis behind these studies has been that infusion of a product containing endothelial progenitor cells (ECs)mayenhance the formation of newblood vessels. Results have shown thatwhile the infusion of these products is safe and feasible, the effect on left ventricular function has been negligible ormodest. The poor responses observed could be related to timing, type andnumber of cells used, route of administration or other variables [1,2]. The formation of blood vessel requires in addition to ECs, other cellular and molecular components, including pericytes, cytokines, chemokines and extracellular matrix molecules (ECM). Pericytes share functional properties and a gene-expression profile with mesenchymal stem cells (MSC). In turn, MSC produce and release angiogenic growth factors and ECM which contribute to the formation of a mature and stable blood vessel [3]. Based on these notions, we hypothesize that a combination, rather a single, cell product consisting of a source of ECs and pericytes could be more effective in promoting the formation of new blood vessels. This phase I clinical study was designed to investigate safety and feasibility after the intracoronary infusion to MI patients of a combination cell product consisting of bone marrow-derived mononuclear cell (BMMNC, a source of ECs) and MSC (a source of pericytes, angiogenic growth factors and ECM). Ten patients were enrolled to be treated with the combination cell product and five patients were used as controls. Table 1 shows main baseline characteristics of study and control patients. Study patients had a primary and secondary iliac crest bone marrow aspiration, 3–4 days after angioplasty and 17±7 days after primary aspiration, respectively. Bone marrow aspirations were not performed to control patients. For preparation of MSC and MNC, the methods previously published were used [4]. The combination cell product for infusion contained 7.5×10 MSC and 7.5×10 MNC (the content of EC-like cells in MNC measured as CD45 cells expressing antigens CD34, CD133 or CD144, was 3.5±1.1%.) After assessment of lot-release criteria (USP sterility, endotoxin, mycoplasma and Gram's stain), the combination cell product was intracoronary infused to study patients. After infusion, coronary angiography, ECG, chemistry panel, complete blood count (CBC) and Troponin I was performed. The average time between onset of MI and angioplasty was 15.7± 14 h. Bone marrow aspiration to initiate the preparation of BM-MSC was performed 3.7±1.8 days after PCI. In turn the cell product or placebo solution was infused 17.2±3.8 and 14.3±1.2 days after MI onset, respectively (Table 1). Intracoronary cell infusion probed to be safe and feasible and did not result in ischemia or infarction in the treated areas. Troponin I remained normal in all subjects at 24 h and 14 days post-infusion. Left Ventricular Ejection Fraction (LVEF)was evaluated in both study and control patients using quantitative gated SPECT at months 1 and 3. Echocardiography was utilized to evaluate ejection fraction and wall motion abnormalities. Table 2A shows data for LVEF at baseline and three months after cell/placebo infusion. No significant changes in LVEF or wall motion (not shown) were detected in either group. Assessment of myocardial ischemiawas performed using non-gated SPECT images myocardial perfusion summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS). As seen in Table 2B, in the group of study patients no differences were observed between SSS and SRS at baseline and month 3 after cell infusion. However, this was not the case for SDS since in all treated patients, baseline scores were considerable higher than those at month 3. In turn, in control patients SSS, SRS and SDS values were comparable at baseline and month 3 after placebo infusion. This phase I studywas designed to assess the feasibility and safety of the intracoronary infusion of a combination cell product to MI patients. Feasibility was demonstrated by the procedural ability to initiate MSC manufacturing 3.7±1.8 days after angioplasty. In turn, the safe preparation and infusion of the cell products were confirmed by the inclusive fulfillment of release criteria and by the absence of adverse clinical events, up to 6 months after cell infusion. These observations corroborate results of our previous animal study showing safe and workable use of the combination cell product [5].
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May 14, 2024
Arundhati Das + 2
Open Access