Unmodified autologous stem cells at point of care for chronic myocardial infarction

Abstract

BACKGROUNDNumerous studies investigated cell-based therapies for myocardial infarction (MI). The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI. Experimental studies on animal models demonstrated the potential of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) for treating acute MI. In contrast, studies on the treatment of chronic MI (CMI; > 4 wk post-MI) with UA-ADRCs have not been published so far. Among several methods for delivering cells to the myocardium, retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.AIMTo test the hypothesis that in experimentally-induced chronic myocardial infarction (CMI; > 4 wk post-MI) in pigs, retrograde delivery of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) into a temporarily blocked coronary vein improves cardiac function and structure.METHODSThe left anterior descending (LAD) coronary artery of pigs was blocked for 180 min at time point T0. Then, either 18 × 106 UA-ADRCs prepared at “point of care” or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0 (T1). Effects of cells or saline were assessed by cardiac magnetic resonance (CMR) imaging, late gadolinium enhancement CMR imaging, and post mortem histologic analysis 10 wk after T0 (T2).RESULTSUnlike the delivery of saline, delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1 (all values given as mean ± SE): Increased mean LVEF (UA-ADRCs group: 34.3% ± 2.9% at T1 vs 40.4 ± 2.6% at T2, P = 0.037; saline group: 37.8% ± 2.6% at T1 vs 36.2% ± 2.4% at T2, P > 0.999), increased mean cardiac output (UA-ADRCs group: 2.7 ± 0.2 L/min at T1 vs 3.8 ± 0.2 L/min at T2, P = 0.002; saline group: 3.4 ± 0.3 L/min at T1 vs 3.6 ± 0.3 L/min at T2, P = 0.798), increased mean mass of the left ventricle (UA-ADRCs group: 55.3 ± 5.0 g at T1 vs 71.3 ± 4.5 g at T2, P < 0.001; saline group: 63.2 ± 3.4 g at T1 vs 68.4 ± 4.0 g at T2, P = 0.321) and reduced mean relative amount of scar volume of the left ventricular wall (UA-ADRCs group: 20.9% ± 2.3% at T1 vs 16.6% ± 1.2% at T2, P = 0.042; saline group: 17.6% ± 1.4% at T1 vs 22.7% ± 1.8% at T2, P = 0.022).CONCLUSIONRetrograde cell delivery of UA-ADRCs in a porcine model for the study of CMI significantly improved myocardial function, increased myocardial mass and reduced the formation of scar tissue.

Safety and Efficacy of Treating Symptomatic, Partial-Thickness Rotator Cuff Tear with Fresh, Uncultured, Unmodified, Autologous Adipose Derived Regenerative Cells (UA-ADRCs) Isolated at Point of Care: A Prospective, Randomized, Controlled First-in-Human Pilot Study

“…Then, the wounds were closed using adhesive bandage strips (Curity or Dermacea Abdominal Pad; Covedian, Mansfield, MA, USA). The harvested lipoaspirate (50 ml per subject) was processed with the Transpose RT / Matrase system (InGeneron, Houston, TX, USA) [18][19][20][21] to isolate UA-ADRCs. The lipoaspirate was divided into two aliquots of 25 ml each.…”

“…The excellent safety profile of treating sPTRCT with UA-ADRCs presented here, which was the primary clinical outcome of this study, was based on the following three pillars: (i) application of UA-ADRCs rather than other types of stem cells; (ii) enzymatic rather than non-enzymatic isolation of UA-ADRCs; and (iii) use of the Transpose RT / Matrase system (InGeneron; [18][19][20][21]) rather than other systems for enzymatic isolation of UA-ADRCs. With respect to the second and third pillar, Aronowitz and colleagues [35] proposed to judge a system or method for isolating UA-ADRCs by the following factors: nucleated cell count, nucleated cells per milliliter of tissue processed, cellular viability, level of residual enzymatic activity, data from flow cytometry and CFU-F assay, infection control, ease of use, cost to operate, and processing time.…”

“…Accordingly, it is not possible to experimentally (or even clinically) determine whether the following benefits of ASCs also apply to UA-ADRCs, although it is reasonable to hypothesize that this is indeed the case. Specifically, ASCs can stay locally, survive and engraft in the new host tissue into which the cells were applied [38], differentiate under guidance of the new microenvironment into cells of all three germ layers [19], integrate into and communicate within the new host tissue by forming direct cell-cell contacts [18], exchange genetic and epigenetic information through release of exosomes [18], participate in building new vascular structures in the host tissue [19,21], positively influence the new host tissue by release of cytokines (among them vascular endothelial growth factor and insulinlike growth factor 1) [39], protect cells at risk in the new host tissue from undergoing apoptosis [39] and induce immune-modulatory and anti-inflammatory properties [40,41]. In any case, the combination of these mechanisms of action apparently render UA-ADRCs more powerful in the treatment of sPTRCTs than corticosteroid.…”

“…Recent studies demonstrate the advantages of newer proprietary methods for harvesting and isolating stem cells [18][19][20][21]. The present study evaluated the safety and efficacy of treating sPTRCT which did not respond to traditional nonoperative care for six weeks with a single injection of UA-ADRCs isolated at point of care.…”

Safety and efficacy of treating symptomatic, partial-thickness rotator cuff tears with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated at the point of care: a prospective, randomized, controlled first-in-human pilot study

“…Recent studies demonstrate the advantages of newer proprietary methods for harvesting and isolating stem cells [27][28][29][30]. This pilot study evaluated the safety and efficacy of treating symptomatic, bursal-sided, and articular-sided PTRCT (sPTRCT) which did not respond to physical therapy treatments for at least 6 weeks with a single injection of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated at the point of care (i.e., at the same location where harvesting of adipose tissue and injection of UA-ADRCs were carried out).…”