Mesenchymal stem cell secretome and exosomes as potential advanced therapy medicinal products for treating a failing heart

Table 1 Pre-clinical studies using mesenchymal stem cell-derived secretome in small and large experimental animal models for cardiac regeneration and repair

Ref.	Model	Source	Isolation methods	Conditioned medium	ROA	Dose and groups	Further details
Timmers et al[59], 2011	Dalland landrace pigs (LCX ligation MI)	hESC-derived MSCs	Centrifugation and 220 nm filtration	Not explicitly mentioned	ICI	MSC-CM, non-CM	CM treatment enhanced cardiac function after MI and suggested potential paracrine-mediated cardioprotection
Hynes et al[67], 2013	Female landrace pigs (LAD occlusion MI)	Porcine EPCs	Centrifuged at 600 × g for 5 minutes + 0.2 μm filtration	IGF-1	ICI	4 mL of X-vivo (control). CM, CM + anti-IGF-1 antibody. CM + Ig. X-vivo + anti-IGF-1 antibody	The data showed IGF-1 as a key mediator of CM’s anti-apoptotic and pro-angiogenic benefits when delivered via ICI
Pavo et al[65], 2014	Porcine (LAD occlusion MI)	Porcine PBMCs (APOSEC)	Dialysis and lyophilization	Not explicitly mentioned	IMI	APOSEC (resuspended in 4 mL physiologic saline, 300 μL aliquots) after 30 days from MI	APOSEC treatment showed long-term improvement in LV pump function, suggesting therapeutic benefits independent of cell differentiation
Vilahur et al[66], 2017	Pigs (LAD ligation MI)	Porcine ASCs	Centrifuged and filtered	GFP	CM: IV. ASCs: ICI (77)	(1) ASCs (1 × 107 cells); (2) CM (30 mL); (3) ASCs + CM; and (4) Control (PBS 30 mL). All of them, 7 days after MI	Explored ASCs and their CM. The ASC-CM group exhibited enhanced micro-vascularization, overcoming ischemia-induced vessel rarefaction
Ellis et al[68], 2021	Mouse exposed to cold UW cardioplegic solution	ASC-S	ASC-S was centrifuged and then filtered using 3 kDa cutoff filters	Antioxidant SOD3, catalase, HGF, VEGF, and SDF-1	I/C infusion of UW ± ASC-S	10% ASC-S in UW solution. Control groups: UW alone or UW + basal media (ASC-BM)	ASC-S significantly improved cardiomyocyte survival, demonstrating its protective role in I/R injury
Könemann et al[64], 2020	Mice (cyclin T1 induced LV-hypertrophy	Murine Sca-1+ & Sca-1- CPCs	0.22 μm filtration + centrifuged for 10 minutes at 300 × g	Not mentioned	IV	Sca-1+ control; Sca-1- control; Sca-1+ Aldo; Sca-1- Aldo, untreated	Sca-1+ CM showed superior cardioprotection, reducing hypertrophy and fibrosis, though both cell types contributed to functional recovery
Huang et al[69], 2020	SD rat (LAD ligation MI) & Yorkshire pigs (LAD ligation MI)	hCSCs	Centrifuged at 1000 × g for 10 minutes	VEGF, HGF, and IGF	TS	artCP (diameter = 3.5 cm patch)	The patch improved myocardial repair by paracrine effects and structural support in rat model. The hCSC-seeded artCP (3.5 cm patch) was implanted via TS. The patch, which releases VEGF, HGF, and IGF, significantly improved cardiac function, demonstrating its scalability for clinical applications

ROA: Route of administration; LCX: Left circumflex; MI: Myocardial infarction; hESC-derived MSCs: Human embryonic stem cell-derived mesenchymal stem cells; ICI: Intra-cardiac injection; CM: Conditioned medium; LAD: Left anterior descending; EPCs: Endothelial progenitor cells; IGF-1: Insulin-like growth factor 1; PBMCs: Peripheral blood mononuclear cells; APOSEC: Apoptotic cell secretome; LV: Left ventricular; ASCs: Adult stem cells; GFP: Green fluorescent protein; IV: Intravenous injection; PBS: Phosphate-buffered saline; UW: University of Wisconsin Solution; ASC-S: Adult stem cell-derived secretome; SOD3: Superoxide dismutase 3; HGF: Hepatocyte growth factor; VEGF: Vascular endothelial growth factor; SDF-1: Stromal cell-derived factor 1; I/C: Intra-corporeal; hCSCs: Human cardiac stem cells; TS: Tissue section; artCP: Articular cardiac patch.