title: Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice.
abstract: Pre-eclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality, and there are no effective clinical treatments for pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, cytoprotective and regenerative properties, secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with pre-eclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment.
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Texas A&M Health Science Center/Baylor Scott & White Health, 702 SW HK Dodgen Loop, Temple, TX, U.S.A.
authors.forename: Piyali
authors.initials: P
authors.lastname: Chatterjee
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Texas A&M Health Science Center/Baylor Scott & White Health, 702 SW HK Dodgen Loop, Temple, TX, U.S.A.
authors.forename: Valorie L
authors.initials: VL
authors.lastname: Chiasson
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Pinzur
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Raveh
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Department of Pathology, Texas A&M Health Science Center/Baylor Scott & White Health, Temple, TX, U.S.A.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Texas A&M Health Science Center/Baylor Scott & White Health, 702 SW HK Dodgen Loop, Temple, TX, U.S.A.
authors.forename: Kelsey R
authors.initials: KR
authors.lastname: Bounds
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Racheli
authors.initials: R
authors.lastname: Ofir
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Flaishon
authors.affiliation: Pluristem Therapeutics Inc., Haifa 31905, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Chajut
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Texas A&M Health Science Center/Baylor Scott & White Health, 702 SW HK Dodgen Loop, Temple, TX, U.S.A. bmitchell@tamhsc.edu.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001794:Blood Pressure; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005865:Gestational Age; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D019899:Paracrine Communication; D010920:Placenta / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D011070:Poly I-C; D011225:Pre-Eclampsia / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011247:Pregnancy; D011804:Quinolines; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D014664:Vasodilation
chemical_list: C557465:1-(2-methylpropyl)-1H-imidazo(4,5-c)quinolin 4-amine; D016207:Cytokines; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D011804:Quinolines; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D011070:Poly I-C
keywords: Toll-like receptors; hypertension; immunity; pre-eclampsia; vascular diseases