Table 3.

Preclinical studies of stem cell therapy for pulmonary hypertension.

Models	Cell type	Route of administration	Pulmonary effect	Direct / indirect RV effect	Found cell engraftment	Study primarily designed for RV effects	Authors
Pre clinical study
MCT rats	EPC	Intravenous	↓connexin43, eNOS expression, ↑ alveolar sacs, ↑ small lung arterioles	Indirect. ↓RVSP, ↓ RVH, ↓ connexin43, eNOS expression	In pulmonary arterioles	No	Yip et al., 2008
			↑ n small lung arterioles, ↓ pulmonary arteriole muscularization	Indirect. ↓RVSP, ↓ RVH	In small pulmonary arterioles	No	Xia et al., 2009
			↓ pulmonary arteriole muscularization	Indirect. ↓RVSP, ↓ RVH	In lung tissue after 15 min but not 24h after injection	No	Ormiston et al., 2009
			ø	ø	ø	No	Mirsky et al., 2011
	EPC producing prostacyclin	Intravenous	↓ pulmonary vessel wall thickening, ↓ cell proliferation in pulmonary vessel wall	Indirect. ↓RVSP, ↓ RVH	In lungs up to 25 days	No	Zhou et al., 2013
	eNOS transduced EPC	Intravenous	↓ pulmonary arteriole muscularization, ↑ microvascular perfusion	Indirect. ↓RVSP, ↓ RVH	In distal arterioles	No	Zhao et al., 2005
	EPC + sildenafil	Intravenous	↑ alveolar sacs, ↑ small lung arterioles, ↓ apoptic and inflammatory biomarkers	Indirect. ↓ apoptic and inflammatory biomarkers, ↓RVSP, ↓ RV weigh	ø	No	Yen et al., 2013
	EPC + cilostazol	Intravenous	↑ alveolar sacs, ↑ small lung arterioles	Indirect. ↓ connexin43, eNOS expression, ↓RVSP, ↓ RV weigh	In pulmonary arterioles	No	Sun et al., 2009
	MSC	Intravenous	↓ thickening of arterioles and alveolar septa	Indirect. ↓RVDP, ↓ RVH, ↓ RVEF	ø	No	Umar et al., 2009
			↓ media wall thickness, ↓ intra-acinar muscular pulmonary arteries	Indirect. ↓ RVP, ↓ RVH, ↓ mRVP	Lung tissue	No	Lee et al., 2015
			↓ media wall thickness, ↑ capillary density	Indirect. ↓RVSP, ↓RVH	Pulmonary vessels	No	Yuelin Zhang et al., 2012
		Intratracheal	↓PAP, ↓PVR	Indirect. ↓ RVH	Lung	No	Baber et al., 2006
	MSC primed with S1P	Intravenous	↓ pulmonary vascular wall thickness, ↑ capillary density	Indirect. ↓RVSP, ↓ RV/(LV+S)	ø	No	Kang et al., 2015
	MSC expressing Heme Oxygenase-1	Intravenous	↓ media wall thickness, ↓ inflammation	Indirect. ↓RVSP, ↓ RVH	Lung	No	Liang et al., 2010
	MSC overexpressing eNOS	Intravenous	ø	Direct. ↓RVSP, ↓ RV weight/body weight	ø	No	Kanki Horimoto et al., 2006
	ADSC	Intravenous	↓mPAP, ↓wall/lumen thickness, ↓wall/lumen area	Indirect. ↓RVH	Lung tissue	No	Luo et al., 2014
	ADSC expressing COX-1	Intratracheal	↓mPAP, ↓ vascular remodeling	Indirect. ↓RVH, ↓RV mass	Lung parenchyma	No	Somanna et al., 2014
	iPS cells	Intravenous	↓wall/lumen thickness, ↓lung tissue inflammation (IL-1β, IL-6, IL-12, IL-23, IFNγ)	Direct. ↓RVH,↓RVSP	Lung parenchyma	No	Huang et al., 2016
Left to right shunt rat	MSC	Intravenous	↓mPAP, ↓ media thickness, ↓ intima thickness, ↓ pulmonary arteries luminal area, ↓ inflammation factors	Indirect. ↓RV/(LV+S), ↓RVSP, ↓mRVP, ↓RV/body weight	ø	No	Luan et al.
LV pressure overload with biventricular failure in rat	MSC	Intracoronary	ø	Direct. ↓RVSP, ↓RVDP, ↓ inflammation, apoptosis and ECM remodeling markers	ø	No	Molina et al., 2008
RV volume overload piglet	CPC	Epicardial	ø	Direct. ↓ in peri-myocytes fibrosis, protection against arrhythmia	No cell survival in RV at 3 months	No	Lambert et al., 2015
RV volume overload sheep	MNC	Epicardial	ø	Direct. Improved RV diastolic function under dobutamine stress, ↑ capillary density	ø	No	Yerebakan et al., 2009