Current perspectives on regenerative potential of mesenchymal stem cells in alleviating cardiac injuries: Molecular pathways and therapeutic enhancement

Table 1 Mechanism of action of mesenchymal stem cells in cardiovascular diseases

Type of mesenchymal stem cells	Human/animal study	Therapeutic role of the used stem cells	Mechanism of activation/enhancing stem cell action	Ref.
Bone marrow mesenchymal stem cells	Mice model	Paracrine secretion of pigment epithelium-derived factor	Using younger mesenchymal stem cells	[92]
Cord blood-derived human mesenchymal stem cell	Rat model	Formation of cardiomyocyte-like cells	Induction of differentiation into cardiomyocyte-like cells	[38]
Human mesenchymal stem cells	Canine animal model	Formation of three-dimensional spheroids	Induction of differentiation and formation of three-dimensional spheroids	[37]
Bone marrow mesenchymal stem cells	Yorkshire swine animal model	Cardiogenesis	Not activated	[93]
Adult human bone marrow mesenchymal stem cells	Human study	Reducing arrhythmia, promoting angiogenesis and tissue perfusion	Not activated	[40]
Human adipose tissue derived mesenchymal stem cells	Yorkshire cross domestic pigs	Immunomodulation and promoting angiogenic	Not activated	[41]
Rat bone marrow mesenchymal stem cells	Rat model	Immunomodulation	Cyclooxygenase-2 overexpressing cells	[42]
Rat and human bone marrow mesenchymal stem cells	Rat model	Immunomodulation	Sug1 knockdown MSCs	[94]
Mice bone marrow mesenchymal stem cells	Mice model and in vitro study	Immunomodulation	Not activated	[28,29]
Human mesenchymal stem cells	Rat model and in vitro study	Immunomodulation and differentiation into smooth muscle-like cells	LL-37-activated	[35]
Human mesenchymal stem cells	C57BL/6J mice	Inhibition of pyroptosis and immunomodulation	Not activated	[54]
Human umbilical cord blood-derived mesenchymal stem cells	cTnT (R141W) transgenic mouse and in vitro study	Cardiac regeneration, pro-angiogenesis, antifibrosis, and anti-apoptotic	In vivo (unconditioned); in vitro (hypoxic conditioning)	[52]
Rat bone marrow mesenchymal stem cells	Rat study	Angiogenesis and muscle regeneration	Not activated	[58]
Human umbilical cord blood-derived mesenchymal stem cells	Mice study	Attenuating pulmonary artery remodeling	Not activated	[62]
Wharton's jelly-derived mesenchymal stem cells	Human study (patients with ST elevation myocardial infarction)	Cardiogenesis	Not activated	[95]
Bone marrow mesenchymal stem cells	Human study (patients with acute myocardial infarction)	Cardiogenesis, immunomodulation, and pro-angiogenesis	Autologous cells, not activated	[96]
Adipose tissue derived mesenchymal stem cells	Rat study	Antioxidant and anti-apoptotic effect	Resveratrol activated	[97]
Umbilical cord-derived mesenchymal stem cells	Human study	Immunomodulatory effects	Not activated	[31]
Autologous mesenchymal stem cells or bone marrow mononuclear cells	Human study	Cardiogensis and antifibrotic	Not activated	[98]
Bone marrow mesenchymal stem cells	Rat study (both in vivo and in vitro)	Differentiation into functional beta-cells, restoration of glucose homeostasis, and antioxidant effect	Resveratrol-activated	[99]
Bone marrow mesenchymal stem cells	Rat study	Pro-angiogenesis, gap junction formation, and improving survival	Ang II-activated	[100]
Bone marrow mesenchymal stem cells	Rat study	Antiapoptotic effects, pro-angiogenesis, and anti-fibrotic effects	Not-activated and resveratrol-activated	[56]
Mesenchymal stem cells from various sources	Human and animal (diabetic rat models)	Antiapoptotic effects and improving proliferation and cell survival	Resveratrol-activated	[101]

Table 2 Differential expression of specific stem cell markers

Adhesion molecules and growth factors	Differential expression	Ref.
CD11c (lymphocyte function-associated antigen 1)	Similar expression in both adipose tissue-derived mesenchymal stem cells and bone marrow mesenchymal stem cells	[133]
CD31 (platelet endothelial cell adhesion molecule)	Similar expression in both adipose tissue-derived mesenchymal stem cells and bone marrow mesenchymal stem cells	[133]
	Not detected in either adipose tissue-stromal or bone marrow mesenchymal stem cells	[134]
CD34	Bone marrow mesenchymal stem cells were negative, while adipose tissue-stromal cells were positive	[134]
	Low expression by adipose tissue-derived mesenchymal stem cells and no detection by bone marrow mesenchymal stem cells	[133]
CD44	Similar expression in both adipose tissue-derived mesenchymal stem cells and bone marrow mesenchymal stem cells	[134]
CD49d (integrin α4)	Found in adipose tissue-derived mesenchymal stem cells, while bone marrow mesenchymal stem cells did not	[133]
CD54 (intercellular adhesion molecule 1)	Adipose tissue-derived mesenchymal stem cells expressed high levels, while bone marrow mesenchymal stem cells had minimal expression	[134]
CD106 (vascular cell adhesion protein 1)	Bone marrow mesenchymal stem cells were positive, while adipose tissue-derived mesenchymal stem cells were negative	[134]
CD191 (C-C chemokine receptor type 1)	Expressed in human adipose tissue-derived mesenchymal stem cells more than bone marrow mesenchymal stem cells	[135]
Chemokines receptor types 1, 4, 6, and CX3C motif chemokine receptor 1	Not detected in bone marrow mesenchymal stem cells compared to relevant expression in adipose tissue-derived mesenchymal stem cells	[135]

Table 3 Exosome treatments in several preclinical models of cardiovascular disease

Cardiac injury	Isolation method	Dose	Number of injections/timing of injections	Route	Ref.
Ischemia/reperfusion	High-performance liquid chromatography	0.4-0.8 μg	Single dose/5 minutes prior to reperfusion	In the perfusion fluid ex-vivo	[89]
Ischemia/reperfusion	High-performance liquid chromatography	0.4 μg	Single/5 minutes prior to reperfusion	Intravenous injection	[235]
Myocardial infarction	Purification from conditioned media	2 × 1011 particles	Single/tail-vein 3 hours after reperfusion	Intravenous injection	[254]
Myocardial infarction	ExoQuick-TC system	Harvested from 4 × 106 MSCs	Single/following left anterior descending artery ligation	Intramyocardial injection	[258]
Myocardial infarction	Exosome isolation reagent (#4478359, Thermo Scientific, San Jose, CA, United States)	5 μg	Single/injected 30 minutes after left anterior descending artery ligation (at three sites of the border zone of the infarcted area)	Intramyocardial injection	[259]
Myocardial infarction	ExoQuick-TC system	80 μg	Single/injected 60 minutes after left anterior descending artery ligation (at four sites of the border zone of the infarcted area)	Intramyocardial injection	[236]
Myocardial infarction	Ultrafiltration method	1 × 1011 particles/kg body weight	Multiple/7 consecutive days after myocardial infarction	Inhalation	[235]
Doxorubicin/trastuzumab-induced cardiac toxicity	Purified exosomes filtered through a 0.2 mm membrane NTA technology	3 × 1010 particles	Multiple/at days 5, 11, and 19 of the experiment	Intravenous injection	[260]

MSC: Mesenchymal stem cell; NTA: Nanoparticles tracking analysis.