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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development


Mouse bone marrow cells reduce miscarriage?

Progenitor cells are like stem cells, but differentiated by a first step into one specific cell type. Research now finds the progenitor cells in bone marrow — which replace worn out cells — may help placental blood vessel growth and reduce abnormal placental development such as in pre-eclampsia.

In a study focussed on self-donated or autologous bone marrow Endothelial Progenitor Cells (EPCs), researchers in Japan discovered that transplanted into pregnant mice, EPCs improve blood vessel growth. EPCs help in the formation of a "normal" placental vascularization (blood vessels), leading to reduced recurring miscarriages.

The study is published in Cell Transplantation.

"We found the vascular pattern in miscarried placentas to be irregular, and blood vessel size small when compared with that of normal gestation. This suggests that autologous EPC therapy may be able to prevent miscarriage in high-risk pregnancies by normalizing vascular patterns and increasing blood vessel size."

Dr. Masaaki Ii, MD PhD, Division of Research Animal Laboratory and Translational Medicine Research Center, Osaka Medical College, Osaka, Japan and study co-author.

Researchers found in a mouse model, the rate of miscarriage was over 20 percent in a group not transplanted with EPCs and only five percent in a group receiving EPCs. They concluded transfused EPCs worked to normalize uterine blood vessels in the placenta which reduced the rate of miscarriage.

One of the key molecules underlying recurrent miscarriageis sFlt1, a soluble receptor for vascular endothelial growth factor (VEGF). Imperfect placental development may produce sFlt-1 and inhibit positive growth factors. They believe transplanted EPCs may work to reduce the negative effect of sFlt-1.

In vitro experiments in mice using soluble Flt-1 cultured in EPCs, suggests that vascular abnormalities could be partly due to inhibition of eNOS or nitric oxide synthase. eNOS is primarily responsible for the generation of nitric oxide (NO) in the vascular endothelium, a single layer of flat cells lining the interior surface of all blood vessels. This layer of cells interfaces between circulating blood and the blood vessel wall. In preeclampsia, placental angiogenesis (blood vessel formation) is imperfect which leads to hypoxia - a deficiency in the amount of oxygen able to reach placental tissues.

Dysregulation of pro- and anti-angiogenetic factors — factors that can destroy or interfere with the creation of the placenta's fine network of blood vessels — causes elevated systemic blood pressure, constriction of blood vessels and hypertension in clinical preeclampsia.

"Autologous EPC transfusion could be a novel therapy to prevent miscarriage in high-risk pregnancies," conclude the researchers. "To establish a safe and feasible EPC therapy, further investigation is needed to explore the mechanism for dysfunctional placental formation and the potential beneficial effect of EPCs."

"Currently, the treatments for high risk pregnancies are largely preventative and may include use of antihypertensive drugs. Autologous EPC transplantation is appealing in that it may be associated with fewer side effects and with a reduced autoimmune response. Establishing safety of this method and determining the particular mechanisms by which EPCs are effective will be integral in moving forward with this therapy."

Amit N. Patel MD MS, Associate Professor, Division of Cardiothoracic Surgery, University of Utah School of Medicine, Director of Clinical Regenerative Medicine and Tissue Engineering, University of Utah.

Bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to not only angiogenesis in ischemic tissue but also neovascularization in uterine endometrium formation. Reduced neovascularization and elevation of serum soluble Flt-1, a functional blockage of VEGF, in the development of placenta is thought to be one of the major causes of repeated miscarriages in gestation. We then examined whether transfusion of VEGF expressing extrinsic EPCs prevented frequent miscarriage via its promotional effect on neovascularization with a VEGF-eNOS signaling pathway in a mouse miscarriage model. The results showed that systemic EPC transfusion significantly reduced the rate of miscarriage, and EPCs were frequently observed in the miscarriage placenta. In contrast, only a few EPCs were detected in the placenta of normal gestation. The vascular pattern was irregular and vessel size was small in the miscarriage placenta compared with that of normal gestation. The placental vascular pattern in miscarriage tended to be normalized with increased vessel size up to the similar level in normal gestation by EPC recruitment. For the mechanistic insight, since soluble Flt-1 inhibits EPC functions, it was suggested that the increased soluble Flt-1 could suppress the recruited EPC functional activity in the miscarriage placenta. In vitro experiments by soluble Flt-1 treatment in cultured EPCs suggested that the vascular abnormality could be partly due to the inhibition of eNOS expression by the increased amounts of soluble Flt-1. These findings of animal experiment indicated that autologous EPC therapy may be a novel therapy to prevent miscarriage in high-risk pregnant with such as preeclampsia.

Keywords: Bone marrow-derived stem cells (BMSCs); Endothelial progenitor cells (EPCs); Miscarriage; Placenta; Vascular development

Citation: Kanki K, Ii M, Terai Y, Ohmichi M, Asahi M. Bone marrow-derived endothelial progenitor cells reduce recurrent miscarriage in gestation. Cell Transplant. Appeared or available on-line: August 5, 2016.

The Co-Editors-in-Chief for CELL TRANSPLANTATION are at the Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA and the Center for Neuropsychiatry, China Medical University Hospital, TaiChung, Taiwan. Contact: Paul R. Sanberg at psanberg@health.usf.edu, Shinn-Zong Lin at shinnzong@yahoo.com.tw, or Associate Editor Samantha Portis at celltransplantation@gmail.com
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Sep 23, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Nitric Oxide (NO) in the vascular endothelium layer of flat cells lining the interior surface
of all blood vessels. In preeclampsia, hypoxia is a deficiency in the amount of oxygen
transferred between these two surfaces. Lack of oxygen negatively affects the placenta.
Image Credit: Biochemical Society Transactions



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