Cell Size Critically Determines Initial Retention of Bone Marrow Mononuclear Cells in the Heart after Intracoronary Injection: Evidence from a Rat Model

Abstract

Intracoronary injection of bone marrow mononuclear cells (BMMNC) is an emerging treatment for heart failure. Initial donor cell retention in the heart is the key to the success of this approach, but this process remains insufficiently characterized. Although it is assumed that cell size of injected cells may influence their initial retention, no scientific evidence has been reported. We developed a unique model utilizing an ex-vivo rat heart perfusion system, enabling quantitative assessment of retention of donor cells after intracoronary injection. The initial (5 minutes after intracoronary injection) retention rate of BMMNC was as low as approximately 20% irrespective of donor cell doses injected (1×106, 8×106, 4×107). Quantitative cell-size assessment revealed a positive relationship between the size of BMMNC and retention ratio; larger subpopulations of BMMNC were more preferentially retained compared to smaller ones. Furthermore, a larger cell type—bone marrow-derived mesenchymal stromal cells (median size = 11.5μm versus 7.0μm for BMMNC)—had a markedly increased retention rate (77.5±1.8%). A positive relationship between the cell size and retention ratio was also seen in mesenchymal stromal cells. Flow-cytometric studies showed expression of cell-surface proteins, including integrins and selectin-ligands, was unchanged between pre-injection BMMNC and those exited from the heart, suggesting that biochemical interaction between donor cells and host coronary endothelium is not critical for BMMNC retention. Histological analyses showed that retained BMMNC and mesenchymal stromal cells were entrapped in the coronary vasculature and did not extravasate by 60 minutes after transplantation. Whilst BMMNC did not change coronary flow after intracoronary injection, mesenchymal stromal cells reduced it, suggesting coronary embolism, which was supported by the histological finding of intravascular cell-clump formation. These data indicate that cell-size dependent, passive (mechanical), intravascular entrapment is responsible for the initial donor cell retention after intracoronary injection of BMMNC in the heart having normal vasculatures (at least).

On-site fabrication of Bi-layered adhesive mesenchymal stromal cell-dressings for the treatment of heart failure

“…Increased initial retention was achieved due to the adhesive nature of fibrin, which enabled the MSC-dressing to firmly adhere to the heart, while securely retaining donor MSCs within. As such, leakage of donor cells early after transplantation, which is a major cause of poor donor cell engraftment using the current methods [ 7 , 8 ], were largely prevented. Since TachoSil Ⓡ is a prefabricated product, the fibrin concentration or crosslinking strength can be changed only marginally between conditions i.e.…”

“…One of the most important issues associated with MSC-based therapy for heart failure is the sub-optimal cell-delivery route [ 2 , 6 ]. While intramyocardial (IM) and intracoronary injections have been commonly used in both pre-clinical and clinical studies, these methods are known to result in poor donor cell engraftment [ 2 , [6] , [7] , [8] , [9] , [10] ]. In addition, these methods carry a risk of complications, such as arrhythmia occurrence and coronary embolism [ 7 , 9 , 11 , 12 ].…”

Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―

“…72,73 Several comparison studies have claimed that AT-MSCs could achieve IC injection, 31 which is a predicted risk from animal models. 32 With regard to therapeutic efficacy, the majority of clinical studies have reported some clinical benefits of BM-MSC treatment, including reduced area of infarction, increased myocardial perfusion, decreased angina frequency, reduced hospitalization period, and clinical status. These favorable effects were observed not only in AMI and ICM patients, but also in nonischemic DCM patients.…”

Fibrin Glue-aided, Instant Epicardial Placement Enhances the Efficacy of Mesenchymal Stromal Cell-Based Therapy for Heart Failure

“…Increased initial retention was achieved mainly by the unique nature of fibrin, which allowed the FG-MSC complex to firmly adhere to the heart, while securely retaining MSCs within. This feature attenuated the initial leakage of donor cells after transplantation, which is a major cause of the poor donor cell engraftment following IM and intracoronary injection 10 , 20 . Our in vivo results revealed that almost all transplanted MSCs were retained at 1 hour after FG-aided epicardial placement, while in contrast less than a half of donor cells were retained after IM injection of the MSC suspension.…”

“…This potentially induces ventricular arrhythmias due to disruption of electrical propagation within the myocardium and re-entry formation 7 , 8 . On the other hand, intracoronary injection carries the risk of coronary embolism, which is particularly critical when infusing MSCs into a diseased and narrowed coronary artery 6 , 9 , 10 .…”