Prematurity/preterm birth is the leading cause of neonatal death in the U.S. and in California. During an average day in California, 149 babies are born preterm. These babies are at increased risk for long-term disabilities, including cerebral palsy, gastrointestinal problems, and vision and hearing loss. Many premature babies also suffer from low birth weight, which not only increases complications in the perinatal period, but also leads to increased cardiovascular disease and diabetes in adulthood. Finally, prematurity and fetal growth restriction are many times the result of obstetric diseases, such as pregnancy-induced hypertension and seizures, which carry high rates of maternal morbidity and mortality. All the above-mentioned diseases result from abnormal development and function of the placenta, which is a transient organ that forms the interface between mother and baby. Trophoblasts are the primary cell type which carries out major placental functions such as establishing blood supply from the mother to the fetus. This application proposes the placenta as a novel target for stem cell therapy and seeks generation of trophoblast stem (TS) cells, which give rise to all subtypes of trophoblasts in the placenta. This research will lead to identification of specific trophoblast markers, which can then be developed into diagnostic tools to use in prenatal screening for placental function and fetal well-being. Most importantly, it will lead to development of trophoblast stem cell-based therapeutics for in-utero intervention in cases of fetal growth restriction, preterm labor, and pre-eclampsia. Prevention of these complications will substantially decrease both neonatal and maternal morbidity and mortality; in addition, treatment of growth restriction in the fetus will in turn decrease cardiovascular disease and diabetes in later life. Thus funding this grant would be a small investment towards substantially improving the health of future generations and alleviating the financial burden caused by premature birth and its complications in California.
The goal of every pregnant mother is to have a healthy baby. Unfortunately, pregnancy can be complicated by many diseases, which affect the placenta, the lifeline of the baby. When the placenta develops abnormally or malfunctions, babies are born small and/or premature. This leads to many complications in the perinatal period, including bleeding and abnormal development of the brain, blindness, and gastrointestinal problems. These complications usually require long stays in neonatal intensive care units, with an average per patient cost of over $20,000, compared to $1,300 for a normal weight term baby in the regular newborn nursery. Even when the small premature baby survives the neonatal period, s/he will face an increased risk of complications as a teenager and later an adult, including cardiovascular disease and diabetes, adding to the already over-burdened healthcare system. But what if we could prevent all these problems before they started, in utero, by treating the placenta? The research proposed in this application could make that possibility a reality, by developing trophoblast stem cells. There is very little known about trophoblast stem cells, because the majority of stem cell research today is focused on embryonic stem cells that become the embryo and give rise to adult organs, like the brain, heart, and pancreas. Virtually nothing is known about the “other” stem cells in the human blastocyst, the trophoblast shell that becomes the placenta. This research would start a whole new direction in the field of stem cell research. It would lead to a greater understanding of placental development and diseases, which many mothers and babies face every day. But most importantly, it would benefit the state of California by leading to therapies aimed at preventing pre-term birth and fetal growth restriction. This will not only improve the health of the future generation of Californians, it would save the state over $200 million annually in neonatal care. Aside from direct contributions towards improving the health of California’s population, funding this grant will contribute to jump-starting careers of not just one, but two physician-scientists, which are extremely rare in the field of perinatal medicine, not just in California, but world-wide. Funding this grant would greatly contribute to the development of two leaders in this field and, through their interactions with other physicians-in-training, lead to attraction of more trainees to research careers in perinatal medicine.
The main cell type comprising the placenta is the trophoblast. This application is focused on elucidating mechanisms of self-renewal and differentiation of human trophoblast stem (TS) cells. The proposal is based on the hypothesis that there is a relationship between hypoxia (here defined as a gas environment with oxygen concentrations below that of air), the expression of p63 and the formation or expansion of placental cell types. Thus, in the first aim the applicant will test this idea and expose cells isolated from placenta to hypoxic conditions and modulate expression of p63. Then, in aim 2, it is proposed to derive TS cells from human embryonic stem cells (hESC). Again the applicant will utilize the idea that hypoxia and modulation of p63 expression can affect the efficiency of the derivation process. Finally, in aim 3, the applicant wishes to identify regulatory factors critical for trophoblast differentiation.
This well written proposal presents a focused project with a straightforward conceptual framework. It targets an important, under-studied area of research that may not only provide therapeutically important approaches to placental defects that cause intrauterine growth retardation, but may also provide new resources for stem cell derivation.
Derivation of TS-like cells under hypoxic conditions from placenta samples is feasible and likely to be successful. As with most primary tissues, lowering the oxygen tension has drastically positive effects on the ability of cells to expand in vitro. However, one reviewer questioned whether assumptions made about the oxygen tension in placental tissue are valid, and another doubted whether hypoxic conditions will specifically promote derivation of proliferating trophoblast cells. Furthermore, some reviewers questioned the assumption that hESC have the capacity to differentiate into TS cells. Even though a number of reports suggest that hESC rapidly differentiate into some extraembryonic lineages, the true nature of these cells is not known. One reviewer pointed out that the only way the field will definitively answer this question is to have scientists dedicated to placental biology working on the problem. A reviewer also questioned the significance of aim 3; even though the proposed microarray studies are doable, it is not clear how the work will contribute to what is already known. Notwithstanding these specific concerns, reviewers appreciated the large potential impact of this work, as this proposal targets the important, yet understudied health issues caused by placental defects.
The applicant is an outstanding physician-scientist and an ideal candidate for a New Faculty Award. S/he started his/her independent position very recently, and has a good publication record, albeit little stem cell experience. The career development plan is well laid out and some of the milestones are very specifically stated. Since the investigator is working in an area with under-represented research effort, s/he is likely to become a leader in this area. The mentors include a preeminent placental scientist, although the nature of the mentoring relationship was not laid out in detail. The institutional commitment was judged to be excellent, including provision of ample space and equipment resources and adequate protection of time for research. The home institution is an excellent academic institution and is increasing its commitment to stem cell research.