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J Cachexia Sarcopenia Muscle. 2018 Oct;9(5):880-897. doi: 10.1002/jcsm.12316. Epub 2018 Sep 19.

Immunomodulatory placental-expanded, mesenchymal stromal cells improve muscle function following hip arthroplasty.

Author information

1
Center for Musculoskeletal Surgery and Julius Wolff Institute, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
2
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
3
Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
4
Pluristem Ltd, Haifa, Israel.
5
Institute of Cell Biology and Neurobiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
6
Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
7
Clinic of Nephrology and Internal Intensive Care Medicine, Charité-Universitaetsmedizin Berlin, Berlin, Germany.

Abstract

BACKGROUND:

No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite their high frequency and associated functional deficits. We sought to address surgical trauma-related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.

METHODS:

Our pilot phase I/IIa study was prospective, randomized, double blind, and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach received an injection of 3.0 × 108 (300 M, n = 6) or 1.5 × 108 (150 M, n = 7) PLX-PAD or a placebo (n = 7) into the injured gluteus medius muscles.

RESULTS:

We did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as Week 6 in the treatment-groups. Surprisingly, until Week 26, the low-dose group outperformed the high-dose group and reached significantly improved strength compared with placebo [150 M vs. placebo: P = 0.007 (baseline adjusted; 95% confidence interval 7.6, 43.9); preoperative baseline values mean ± SE: placebo: 24.4 ± 6.7 Nm, 150 M: 27.3 ± 5.6 Nm], mirrored by an increase in muscle volume [150 M vs. placebo: P = 0.004 (baseline adjusted; 95% confidence interval 6.0, 30.0); preoperative baseline values GM volume: placebo: 211.9 ± 15.3 cm3 , 150 M: 237.4 ± 27.2 cm3 ]. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose treatment (exemplarily: CD16+ NK cells: Day 1 P = 0.06 vs. placebo, P = 0.07 vs. 150 M; CD4+ T-cells: Day 1 P = 0.04 vs. placebo, P = 0.08 vs. 150 M). Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.

CONCLUSIONS:

Allogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.

KEYWORDS:

Biomarkers; Cell therapy; Immunomodulation; Mesenchymal stromal cells; Muscle injury; Muscle regeneration

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