Table 4.

Preclinical studies of mesenchymal stromal (stem) cells in lung disease models

Injury Model	Experimental Model, Route, and Timing of Treatment	MSC Source	MSCs Modified?	Syn Allo or Xeno	Outcome Compared with Injury Effects	Potential Mechanisms of MSC actions	Cell Controls?
Danchuk, 2011 (259)	Mouse: OP (IT) LPS	Mouse BM MSCs Texas (Tulane) MSC Core	siTSG-6 knockdown	Syn	• Dec histo injury 48 h	TSG-6 released by MSCs	IMR 90 lung fibroblasts
	OP MSCs 4 h after LPS				• Dec lung edema 24/48 h		• Do not mimic effects and increase BAL total cell counts and PMNs
	P 1–2				• Dec BAL protein 24 h		MSCs treated with siTSG-6 lose most effects
	2.5 × 105 cells/mouse				• Dec in multiple inflamm cyto and chemokines at 24 h
Kim, 2011 (260)	Mouse: IT E. coli	Human umbilical cord MSCs	No	Xeno	• Inc survival	Nonspecified paracrine effects	Human fibroblasts MRC-5
	IT MSCs 3 h after E. coli	+CD73, v105; −CD 14, 34, 45; +HLA AB; −HLA DR			• Dec histo injury and lung edema Day 3		• Do not mimic effects on survival, edema, cytokines, MPO and increase histologic inflammation
	P 5	osteo/adipo/chrondo			• Dec BAL protein MPO Day 3
	105 cells/mouse				• Dec IL-1α, IL-1β, IL-6, TNF-α, MIP-2 in lung homogenates Bays 3 and 7
					• Dec bacterial CFU in BAL/blood Days 3 and 7
Sun, 2011 (261)	Mouse: IT LPS	Primary human umbilical cord MSCs	No	Xeno	• Dec mortality	Nonspecified soluble mediators	Apoptotic MSCs (mitomycinC treated)
	IT MSCs 4 h after LPS	+CD 29, 44, 73; −CD 34, 45, HLAII			• Dec histo injury (3 d)		• Did not mimic MSC results
	P 5–6	osteo/adipo			• Dec BAL TNF-α, MIP-2, IFNγ (3 d)
	106 cells/mouse				• Inc BAL IL-10 (3 d)
					• Dec BAL Th1 CD4 T cells
					• Inc BAL CD4/CD25/Foxp3 Tregs
Gupta, 2012 (262)	Mouse: IT E. coli	Mouse BM MSCs (Tulane)	No	Syn	• Inc survival 48 h	TNF-α released from alveolar macrophages stimulates lipocalin release from MSCs	3T3 fibroblasts
	IT MSCs 4 h after E. coli				• Dec histo injury 48 h		• Did not mimic any results
	P 5–10				• Inc bacterial clearance
	7.5 × 105 cells/mouse				• Dec BAL MPO, TNF-α, MIP-2 at 8 h
					• No change in BAL IL-10
					• No change in BAL defensins, collectins, SPD
Ionescu, 2012 (264)	Mouse: IT LPS	Mouse BM MSCs	No	Syn	• Dec BAL total cells, PMN	Conditioned media mimicked MSC effects	Primary lung fibroblasts or fibroblasgts conditioned media
	MSCs or CM 4 h after LPS	+Sca1, CD29, 105; −CD11b, 154, 31; −CD 34,44,45; −ckit; −Flk1			• Dec lung edema	Secretome analyses and neutralizing antibodies suggest IGF1 as a responsible mediator	• Did not mimic effects
	P 2–8	Osteo/adipo			• Dec histologic injury
					• Inc M2 phenotype
Islam, 2012 (247)	Mouse: IT LPS	Mouse BM MSCs	1) MSCs from Cx43 mutant mice	Syn	• MSCs localize in alveolar spaces	Mitochondrial transfer from MSCs to type 2 cells	MSC from Connexin 43 mutants and those treated with siRISP
	MSCs 4 h after LPS		2) MSCs treatedwith SiRISP		• Form connexin 43 bridges to type 2 cells		• Did not mimic results 3T3 fibroblasts: down-regulated Cx43 expression
	P 2				• Increased lung (type 2) ATP
	106 cells/mouse				• Improved surfactant production
					• Dec histo injury, albumin leak, BAL inflamm cells
Krasnodembskaya, 2012 (292)	Mouse IT E. coli	Human BM MSCs	No	Xeno	• Dec BAL total cells, PMN, protein, MIP2	LL37 release by MSCs	Human lung fibroblasts
	IT MSCs 4 h after LPS	Texas (Tulane) MSC			• Dec bacterial growth in lung homogenates	Effects lost with use of neutralizing anti-LL37 antibody No release of hBD2 or 3, lipocalin, SPD	• Did not mimic effects
	P 5	Core			• Inc antibacterial activity of BAL fluid
	10 × 106 cells/mouse				• Prestimulated MSC conditioned media decreased bacterial growth in in vitro culture
Nazarov, 2012 (302)	Explant human lung IT	Human BM MSCs	No	Allo	• Normalized alveolar fluid clearance	siRNAs to HGF, KGF, or FGF-β; each partly inhibited MSCs effects	Normal human lung fibroblasts did not mimic effects
	LPS IT MSCs 1 h after LPS	Primary hCMSCs +CD73, 105, 117; +SSEA 3/4; −CD45,133,HLA-DR; +osteo/adipo			• Dec BAL fluid PMN, IL-1β, IL-8
	P < 10				• hCMSCs equivalent to BM-MSCs
	5 × 106 cells				• Partial restoration of fluid transport and permeability in primate AT2 monolayers
					• cMSCs more effective than BM-MSCs
Lee, 2013 (303)	Explant human lung IT E. coli	Human BM MSCs Texas (Tulane) MSC Core	No	Allo	MSCs 1 h after E. coli	KGF mimicked effects	Normal human lung fibroblasts did not mimic effects
	IT or IV MSCs or 1 h after LPS				• Improved fluid clearance
	P < 10				• Dec PMN, IL-1β, IL-8
	5–10 × 106 cells				• Improved histologic injury
					• Inc bacterial killing
					• Dec bacteremia
					• Labeled MSCs migrated to alveolar spaces in injured lungs
					• IV or IT MSCs had equiv effects
					• Inc macrophage bacterial phagocytosis
					• No effect on macrophage phenotype
					MSCs 2 h after higher E. coli dose
					• Improved fluid clearance
					• Dec PMN
					• Dec bacteremeia
					• Additive effects with antibiotic
Zhang, 2013 (265)	Mouse: IT LPS IT MSCs	Mouse or human adipose MSCs −CD11b, 31, 45; +CD29,106 +osteo/adipo	No	Syn and Xeno	24 or 72 h after LPS Improved body weight	Soluble mediators	No
	4 h after LPS				Dec BAL fluid protein and albumin
	P 3				Dec BAL fluid total cells, PMNs, MPO activity
	7.5 × 105 cells/mouse				Dec histo injury
					Dec mRNA (lung homogenates: IL-1α, IL-1β, MIP-1α, MIP-2, TNF-α
					No change in mRNA for IL-10
					Dec lung homogenate IL-1β protein and inc in IL-10 (mMSC only)
					In general mMSC more effective than hMSCs
Asthma
Firinci, 2011 (266)	Mouse: ovalbumin sensitization Days 0, 14, 21	Mouse BM-adherent cells; +CD73, 105; −CD45; no diff info provided	No	Syn	• No engraftment	None (paracrine)	No
	Challenge: ova aerosol 3 d/wk for 8 wk MSCs IV Day 75				• Some dec in histo injury
	P 2
	1 × 106 cells/mouse
	Harvest Day 82 (engraftment?) and Day 89 (lung assessment)				• Dec serum NO
Kapoor, 2011 (268)	In vitro study	Human BM Healthy donors P4–5 +CD29, 44, 105 -CD14, 45-	No	Allo	• Dec PMBC prolif (3[H]-Thymidine)	None (paracinre and cell–cell contact)	No
	Peripheral blood monocyte cells from 7 patients with allergic asthma and four healthy control subjects				• Dec IFN-γ
	Four dust mite sensitive/nonasthmatic				• Inc IL-10
					• Inc PMBC prolif in response to tetanus toxoid
					• No induction of TReg cells
					• Dec DM induced DC maturation
					Precondition
					• Dec response to dust mite antigen
					• Required cell–cell contact
					• Dec response to repeat challenge
Kavanaugh and Mahon, 2011 (269)	Mouse: ovalbumin-induced acute allergic airways inflammation; ovalbumin sensitization Days 0, 7, 14 MSCs IV Days 7/14	Mouse (FVB) BM; +Sca1; low CD44, 106; −CD 11b, 11c, 34,35,117; osteo/adipo/Chondro		Allo	• Dec histo injury	None (paracrine)	PFA-fixed MSCs
	P 4–9				• Dec BAL total cells, Eos, Macs		• No effect on histo, BAL except BAL IL-13
	5 × 106 cells/infusion				• Dec BAL IL-4, IL-13		• Inc splenocyte IL-4, dec splenocyte IL-10, IL-13
	ChallengeDays 25–27; harvest Day 28				• Inc BAL IL-10
					• Dec splenocyte IL-4
					• Inc splenocyte IL-13, IL-10
Lee, 2011 (270)	Mouse toluene disocyanate inhalation induced acute airways inflammation MSCs IV Day	Rat BM MSCs and adherent cells CD44+, CD45+	No	Xeno	• Dec BAL total cells	None	No
	P 8				• Dec BAL macrophage, PMN, Eos
	105 cells/mouse				• Dec histologic injury
					• Dec goblet cells
					• Dec peribronchial collagen and SMA deposition
					• Dec epithelial proliferation
					• Dec airway hyper responsiveness (Penh)
Ou-Yang, 2011 (271)	Mouse: ovalbumin-induced acute allergic airways inflammation	Mouse BM; +CD90, Sca1; −CD44, 45	AMD3100-treated MSCs	Syn	• Dec histo injury	None (paracrine)	AMD3100-treated MSCs retained less in lung
	Ovalbumin sensitization Days 1, 8				• Improved lung mechanics
	MSCs IV Day 12				• Dec BAL total cells, Eos
	P 2–-4;				• Dec BAL fluid b-hexosaminidase
	2 × 106 cells/mouse				• Dec BAL IL-4, IL-5, IL-9
					• Inc BAL IFN-γ
					• Lung homogenate: dec IL-4, inc IFN-γ
Ionescu, 2012 (272)	Mouse ovalbumin; acute model sensitization Days 1, 6; challenge Days 11, 13; harvest Day 15	Mouse BM MSCs CD45+ vs. CD45−	Adiponectin KO MSCs	Syn	• Dec histo injury: acute and chronic	Adiponectin release by MSCs	Primary mouse lung fibroblasts
	Chronic model sensitization Days 1, 8, 15, 29; first challenge Days 22, 24, 27; second challenge Days 31, 33, 36; harvest Day 38		WT MSCs with neutralizing adiponectin Ab		• Dec BAL total cells, Eos, PMN, Macs: acute and chronic		• CM mimics decrease in BAL total cells and PMNs
	MSC-conditioned medium on all challenge days				• Dec airways resistance and elastance: acute dec elastance: chronic		• Does not mimic other effects
	P 2				• Restored salbutamol responsiveness: chronic		APN KO MSCs and si knockdown of APN in wildtype MSCs lose MSC effects
					• Dec BAL IL-4, IL-13; inc IL-10: acute and chronic
					• Promote alveolar mac M2 phenotype
					• Inc Tregs in lung
Bronchopulmonary dysplasia
Chang, 2011 (273)	Neonatal rats: hyperoxia (95% FiO2) × 14 d	Human umbilical cord MSCs from a single donor	No	Xeno	Day 14	Paracrine	No
	IT MSCs postnatal Day 5				• Inc survival
	P 5				• Dec alveolar injury
	103, 104, or 105 cells/rat				• Dec apoptosis
					• Dec myeloperoxidase
					• Dec mRNA TNF-α, IL-1β, IL-6, TGF-β
					• Dose-dependent effect
Piero, 2012 (274)	Neonatal rats: hyperoxia (95% O2) post notes Day 4–14	Human cord blood MSCs	No	Xeno	Prevention	Paracrine	Primary neonatal rat dermal fibroblast
	IT MSCs or Conditioned media Day 4 or Day 14	Human cord blood peri vascular cells			• MSC Day 4/lung harvest Day 22
	P 3	Conditioned media			• Partial preservation of alveolar growth
	6 × 105 cells/rat				• Prevent decrease in lung compliance
					Regeneration
					• MSC Day 14/lung harvest Day 35
					• Restore normal alveolar architecture
					Long term
					• MSC Day 4/lung harvest 6 mo
					• No obvious lesions on CT scans
					• Improved exercise capacity
					Conditioned media
					• Daily, Day 4–Day 21
					• Improved alveolar architecture
					• Improved lung function
					• Attenuated decrease in pulm vasculature
					• Prevented arterial wall remodeling
					• Dec RV hypertrophy
Tropea, 2012 (277)	Neonatal mice: hyperoxia × 14 d		No	Syn	• Inc # of BASCs	Stimulation of endothelial activation?	Pulmonary artery smooth muscle cell and CM did not mimic effects
	IV MSCs on Day 4				• Inc growth and differentiation of BASC	Effects mimicked by MSC conditioned medium
	5 × 104 cells
Zhang H, 2012 (275)	Neonatal rat: hyperoxia × 7 d	Rat BM: +CD29, 44, 90; −CD11b, 34, 45; adipo/osteo	Lentiviral transduced to express GFP	Syn	Reversed weight loss	Paracrine	No
	IV MSCs Day 7;harvest Days 1, 3, 7, 14				Dec histologic injury
	P				Dec TNF-α,TGF-β in lung homogenate
	105 cells/rat				Inc IL-10 in lung homogenate
Zhang X, 2012 (276)	Neonatal mice: hyperoxia × 45 d	Mouse BM: +CD105, 106; −CD34, 45; adipo/osteo	No	Syn	Inc survival	Paracrine	No
	IP MSCs on Day 7; harvest on Day 45				Dec histo injury
	P				Dec TGF-β, Col-1α, TIMP-1 in lung homogenates
	105 cells/mouse				Dec serum IL-1, TNF-α
Wascak, 2012 (249)	Neonatal rats: Hyperoxia (95%) × 14 d	BM MSCs Adipo/Chond/Osteo	MSCs exposed to hyperoxia (95%) for 24 h	Syn	MSC-O2CM > MSC-CM	Soluble mediators STC-1	Primary rat lung fibroblasts Did not mimic effects
	IV MSC conditioned media for 21 d starting on Day 0				Dec pulm HTN, RV hypertrophy
	P				Dec histologic injury
	Cells/rat				Preconditioning of MSCs
					No change in antioxidant capacity
					Inc STC-1 expression
					No change in HGF, KGF, VEGF, IGF expression
Sustsko, 2013 (278)	Neonatal rat: hyperoxia (90%) Day 2–16	BM MSCs from normal and GFP rats	No	Allo	D16 and D30 assessments	Paracrine	No
	MSCs or conditioned media (CM) on D9				Improved pulmonary hemodynamics
	P				Improved oxygenation
	2 × 106 cells/rat				Improved lung function (PenH)
					Dec histo injury/improved alveolarization
					Inc capillary density
					Dec mRNA for IL-1β, IL-6
					Inc mRNA for TTF-1
					MSC = CM
					D100 assessment
					Improved histo injury (MSC > CM)
					Inc capillary density (MSC = CM)
					Improved RVSP (MSC only)
					No effect on RVH
COPD
Hoffman, 2011 (279)	Mouse: IT elastase	Mouse BM (Tulane)	No	Syn	• Higher retention of L-MSCs in lung	Nonpostulated	No
	IV MSCs 6–7 wk after elastase	Lung MSCs from primary explant cultures			• Dec histo injury (MLI) at 22–28 d
	P 7	Flow characterization?
	106 cells/mouse	Adipo/chondro/osteo
Huh, 2011 (417)	Rat: 6-mo cigarette smoke exposure	Total BMCs: freshly isolated and filtered	Male cells into female recipients	Syn	• 2 mo after BMCs	Soluble mediators	CM normal human lung fibroblasts and human pulmonary artery smooth muscle cells did not inc proliferation of the HPAECs
	BM cells, MSCs, or conditioned media	Rat BM MSCs +CD73, 90; −CD34, 45			• Improvement evident after 1 wk
	P 4 MSCs	+adipo/osteo			• Dec histo injury
	6 × 106 BMCs vs. 6 × 105 MSCs/rat	CM from P3–5 MSCs			• Enhanced prolif and dec apoptosis (AT2 and vasc endo cells)
					• Inc aKT phosphorylation
					• Inc KGF
					• Inc number of small blood vessels
					• Dec pulm HTN
					• MSCs and MSC CM had similar effects on improving lung histo and number of small arteries
					• MSCs but not MSC-CM improved pulm HTN
					• MSC CM inc in vitro proliferation of human pulmonary artery endothelial cells
					• No significant engraftment of either BMC or MSC
Schweitzer, 2011 (281)	Mouse: cigarette smoke exposure for 24 wk	Human ASCs Mouse BM MSCs	No	Syn and xeno	• Minimal cell retention in lung dec over time with CS exposure	Paracrine effects	No
	NOD-SCID mouse (for xenogeneic) human ASCs 3 d after VEGFR blockade	Characterization?			• Dec histo injury (MLI, alveolar volume) and caspase activation
	MSCs IV ever other week during last 2 moof CS exposure				• Dec weight loss, inc subcutaneous fat
	P < 3				• Dec BAL mac/PMN
	5 × 105 cell/infusion				• Dec lung homogenate caspase 3, p38 MAPK phos, JNK, AKT
					• Dec CS induced BM suppression
					• Dec VEFGR blockade-induced air space enlargement
					• Human ASCs decreased histologic injury and caspase 3 activation after VEGFR blockade
					• Emboli if used > 5 × 105 MSCs or if > passage 3
					• hASC CM inc wound repair in cultured lung endothelial cells dec with water soluble CS extract
Ingenito, 2012 (234)	Sheep: IT elastase 5 doses over 20 wk	Sheep lung-derived MSCs;	No	Syn	• Inc lung tissue mass and perfusion	Paracrine effects Inc epithelial proliferation in in vitro coculture expts	No
	L-MSCs in fibinogen/fibrin/poly-l-lysine scaffolds	+S100A4 −fibrillin 1; CD45, α-SMA, col I			• Inc histo cellularity, cell retention, ECM
	P 5	Adipo/chrondo/osteo			• Improved lung mechanics
	5–10 × 106 cells/scaff
Kim, 2012 (282)	Mouse: lung fibroblasts; in vitro CSE exposure	Rat BM Plastic adherent	Yes (ISCT)	Xeno Syn	• In vitro CSE exposure	FGF2 release by MSCs	Conditioned media from RF2-6 cells, HFASMCS, NHLFs
	Rats: in vivo cigarette smoke 8-wk rat, 5 d/wk, 6 mo	CM P3–5 from 90% confluent cells			• Dec in CSE induced capsase 3, p53, p21, p27, Akt, p-Akt expression		• Did not mimic effects
	IV MSC or CM 2× wk IV for 5 wk starting at Week 8; killed 3 wk later				• Inc in CSE-induced dec ECM expression and collagen gel contraction
	P 3–5				• Dec in CSE-induced COX-2 and PGE synthase 2 expression
					• PI3K inhibitor partially reversed the effects
					• In vivo CS exposure restored fibroblast proliferation, inc Akt
Katsha, 2011 (280)	Mouse: IT elastase	Mouse BM MSCs; +CD 73, 90, 105; −CD 11b, 45; adipo/osteo	si EGF–treated MSCs	Syn	• Dec histo injury at Days 7,14,21 after MSCs	EGF production by MSCs induces SLPI in cultured MLE-12 cells	BLKCL4 lung fibroblasts
	IT MSCs 14 d after injury				• Dec BAL IL-1β at Days 3 and 5 after MSCs		• Do not mimic effects
	5 × 105 cells/mouse				• Dec IL-1β mRNA in lung homgenates at Days 1,3,5,7 after MSCs
	P 5				• Inc EGF, HGF, and SLPI mRNA at various time points after MSCs
Pulmonary fibrosis
Saito, 2011 (284)	Mouse: IT Bleo IV MSCs 24 h after bleo	Mouse BM	Lentiviral transduction to express CCL2 inhibitor (7ND)	Syn	• Improved survival	Soluble mediator activating CCL2 pathways	No
	P 5–15				• Dec histologic injury
	5 × 105 cells/mouse				• Dec lung collagen
					• Dec BAL inflammatory cells
					• Dec BAL IL-1β, IL-6
					• 7ND-expressing MSCs more effective than MSCs
Lim, 2012 (285)	Mouse: C56Bl/6, SCID IN bleo	Human BM MSCs (Tulane)	No	Xeno	SCID mice	None specified	No
	MSCs IV 24 h after bleo				• Inc body weight
	P 3				• Inc tidal volume/lung mechanics
	1 × 106 cells/mouse				• Dec histo injury
					• Dec lung collagen (hydroxyproline)
					• Dec MIP-1α mRNA
					• Inc TGF-β mRNA
					• Dec CD45+ cells by histo
					C57/BL/6 mice
					• No effect on histo/lung function/collagen/CD45+ cells
					• Dec MIFMIP-1α, TGF-β, TNF-α mRNA
Ischemia-reperfusion Injury
Sun, 2011 (283)	Rats: 30 min clamp of left mainstem bronchus and PA	Rat adipose adherent cells cultured for 14 d.	No	Syn	• Imp oxygenation 72 h	None specified (paracrine effect)	No cell controls
	IV MSCs at 1,6, and 24 h	Likely a heterogenous mix containing MSCs and EPCs			• Dec histo injury 72 h
	P	+CD 29, 31, 34, 90, 271 others as listed in paper			• Lung homogenates PCR
	1.5 × 106 cells/infusion				• Dec IL-1β, TNF-α, MMP-9, Bax, caspase 3, endothelin. Inc eNOS, IL-10, adiponection, heme oxygenase, glutathione reductase, gluthione peroxidase, BCL-2
					• Lung homogenate westerns: dec VCAM-1, ICAM-1, TNF-α, NK-kB, cytosolic cytochrome C, Cx43; Inc HO, mitochondrial cytochrome C
Pulmonary hypertension
Jungebluth, 2011 (288)	Rat: left pulmonary artery ligation	Rat BM	No	Syn	• 12 wk	Paracrine	No
	IT MSCs immediately after ligation				• Improved pulmonary hemodynamics
	P?				• Dec RVH
	6 × 106 cells/rat				• Improved oxygenation
					• Improved lung mechanics (penH)
					• Improved exercise capacity
					• Decreased histo injury
					• Dec liver damage
Liang, 2011 (289)	Mouse: chronic hypoxia 8–10%	Mouse: BM WT mice KO mice	No	Syn	• WT		Lung fibroblasts
	MSCs IV 5 wk to 2 wk	Heme oxygenase			• HO−/−		• Did nott mimic MSC effects
	P	SPC-HO mouse			• SPC HO reverse established disease
	Cells/mouse	Dox-inducible lung Ho-1			Nl RV pressure
					Dec RV hypotrophy
					Prevented RV infarction
					• Dec hypoxic induced inc in MCP-1, IL-6
					• Dec hypoxic induced dec in IL-IR-N
					• CM led to dec PASMC proliferation
Hansmann, 2012 (290)	Mice: hyperoxia × 2 wk	Mouse BM +CD73, 90, 105; +ckit, Sca-1; −CD11b, 14, 19, 31, 34; −CD45, 79α	No	Syn	• 4 wk	Soluble mediators	Primary mouse lung fibroblasts or fibroblasts conditioned medium
	MSCs or CM IV at 2 wk followed by 2–4 wk normoxia				Dec alveolar injury, vascular remodeling		• Did not mimic MSC or MSC-CM effects
	P				Inc number pulm blood vessels
	Cells/mouse				• 6 wk
					Normalized lung function
					Reversed pulm HTN, RV hypertrophy
					Dec peripheral artery muscularization
Lee, 2012 (291)	Neonatal mice: Hypoxia-induced pulm HTN (8.5% O2 × 48 h)	Mouse BM Human cord blood (Wharton’s jelly)	No	Syn	• Mouse MSC CM or exosomes	miRNA-16, -21, let7b transfer via exosomes	Mouse primary dermal fibroblasts
	MSCs, CM, or exosomes before hypoxia				Dec BAL macrophage, MCP-1, HIMF, FIZZ		• CM or exosomes partly decreased injuury
	P				• Mex-depleted media
	Cells/mouse				Didnot mimic effects
					• Two doses (before hypoxia and at 4 d)
					Partial reduction in pulm HTN, RV hypertrophy, lung vascular remodeling
					• Single high dose
					More potent effect
					Dec stat 3, miR-17
					• Human CB MSCs
					Dec stat 3 in pulmonary artery endothelial cells
Sepsis
Krasnodembskaya, 2012 (292)	Mouse: IP P. aeruginosa	Human BM Texas (Tulane) MSC Core	CD13−, CD45−	Xeno	• Inc survival		3T3 fibroblasts
	IV MSCs 18r after P. aeruginosa				• Dec blood CFU PA		• Did not replicate results
	P 3–10				• No change in blood TNF-α, MIP-2, IL-10
	106 cells/mouse				• Inc blood monocyte phagocytic activity
					• Inc C5a
					• Inc spleen M2 (CD163+, CD206+)
					• Inc blood PAI-1
					• Inc platelets
Other critical illness or autoimmune-induced lung diseases: hemorrhagic shock, lupus, silicosis, ventilator-induced lung injury
Curley, 2011 (293)	Rat: injurious ventilation, insp pressure 35 cm, resp rate 18, Peep 0 goal: > 50% dec in static compliance	Primary rate BM MSCs	No	Syn	• Improved oxygenation at 48 h	Soluble mediators as conditioned media mimicked all effects	• Primary rat dermis fibroblasts
	MSCs IV immediately after injury and then again at 24 h				• Improved lung compliance at 48 h	Parallel in vitro studies with human BM MSC CM CM improved A549 wound healing	• Neither fibroblasts or fibroblast CM mimicked effects in vivo
	P				• Dec edema at 48 h	Anti-KGF but not anti-HGFb neutralizing abs abrogated effect
	2 × 106 cells/rat				• Dec histo injury at 48 h
					• Dec BAL protein total cells, PMNs at 48 h
					• Dec BAL TNF-α, inc BAL IL-10 at 48 h
Pati, 2011 (294)	Rats: controlled bleed (hemorrhagic shock)	Lonza primary human MSCs (BM?); +CD44, 105; −CD31	No	Xeno	• Dec histo injury 4 d	MSCs and MSC CM inhibits VEGFA-induced perm in cultured human pulm endothelial cells	No cell controls
	MSCs with fluid resuscitation IV 1 and 24 h after bleed				• Dec lung edema 4 d	Restores β-catenin and VE-cadherin expression MSCs but not MSC
	P 1				• Preserved lung VE chadherin, claudin 1, occludin, and PDFG-β at 4 d	CM inhibit inflamm cell adherence to PECs Dec TNF-α stimulated inc in PEC VCAM-1 and ICAM-1 expression
	2 × 106 cells/dose/rat				• No effect on MAP	Cell–cell contact required
					• Dec serum TNF-α, MCP-1, MIP-1a at 2 h
					• Inc serum IL-10 at 2 h
					• No change in lung or serum cytokines at 96 h
Chimenti, 2012 (295)	Rat (Sprague-Dawley): injurious ventilation, 80 breaths/min at 25 ml/kg Vt	Lewis Rat BM MSCs Texas (Tulane) MSC core	No	Allo	• 3-h analyses	Soluble mediators	No
	IV or IT MSCs 30 min before injurious ventilation				• Dec histo injury
	P 5				• Improved fluid clearance
	106 cells/rat				• Dec BALF total protein, PMN, IL-1β, MIP-2
					• Dec VCAM1 expression on histo sections
					• Inc IL-1-RA mRNA in lung homogenates
					• No effect on HGF or KGF mRNA
					• IT and IV MSCs produce comparable results
Wang, 2012 (297)	Rat: sodium taurocholate-induced acute pancreatitis related ALI	Sprague-Dawly rat BM MSCs	No	Syn	• Dec pulmonary edema	Nonspecified (soluble mediators)	No cell controls
					• Dec histologic lung inflammation
	P 3				• Dec lung MPO activity
	106 cells/rat				• Dec TNF-α and substance P mRNA in lung homogenates

Definition of abbreviations: ASC = adipose-derived mesenchymal stromal cell; ALI = acute lung injury; Ang 1 = angiopoietin 1; BAL = bronchoalveolar lavage; BALF = bronchoalveolar lavage fluid; BASC = bronchoalveolar stem cells; BM = bone marrow; CFU = colony forming units; CM = conditioned media; Dec = decreased; GFP = green fluorescent protein; hASC = human amniotic fluid–derived stem cell; hCMSC = human chorionic stromal cell; HGF = hepatocyte growth factor; histo = histological; HO = heme oxygenase; HTN = hypertension; IM = intramuscular; IN = intranasal; Inc = increaesd; iNOS = inducible nitric oxide synthase; IT = intratracheal; IV = intravenous; KGF = keratinocyte growth factor; KO = knockout; LPS = lipopolysaccharide; MSC = mesenchymal stromal (stem) cell; MIF = migration inhibitory factor; MPO = myeloperoxidase; NOD = nonobese diabetic; OP = oropharyngeal; P = passage; PA = pulmonary artery; PLF = pleural lavage fluid; PMBC = peripheral blood mononuclear cell; Pulm = pulmonary; RV = right ventricular; SPC = surfactant protein C; SSEA = stage-specific embryonic antigen 1; TNF-α = tumor necrosis factor-α; VEGFA = vascular endothelial growth factor A; WT = wild type.