Researcher Spotlights

Grant Project Title:

The Role of Mesenchymal Stem Cells in Recurrent Implantation Failure

Grant Amount:

$50,000

Significance:

Since the advent of IVF over four decades ago, stimulation protocols, embryo culture, transfer techniques, and embryo selection strategies have been optimized. However, our understanding of the implantation process has remained a “black box” as many patients continue to suffer the disappointment of recurrent implantation failure (RIF). In recent years it has become apparent that endometrial factors may be a main etiology underlying RIF but this remains poorly defined. Due to this critical gap in knowledge, the therapeutic approach to RIF has been largely empirical with very limited efficacy. Endometrial mesenchymal stem/progenitor cells provide a major physiological contribution to the remarkable cellular regeneration as well as decidualization that the endometrium undergoes with each menstrual cycle in preparation for embryo implantation but their role in implantation failure is unknown. This project aims to utilize single cell RNA-seq to characterize individual endometrial cell populations including mesenchymal stem cells at a single cell resolution, and characterize their cell-cell interactions at the tissue level to gain novel insights into the cellular and molecular mechanisms that underlie RIF endometrial pathology.

The ASRM Research Institute grant has been instrumental in providing me with essential funding at a crucial step in my career development as a physician-scientist. This grant support helped me to generate extensive high-throughput preliminary data which served as an important basis for my RO1 grant application allowing me to obtain independent NIH funding supporting my successful transition to independence. I am truly grateful to the ASRM Research Institute for their vision and unwavering commitment to support physician-scientists in our field.

Reshef Tal, MD PhD
Assistant Professor
Division of Reproductive Endocrinology & Infertility
Department of Obstetrics, Gynecology & Reproductive Sciences
Yale School of Medicine

Grant Project Title:

Defining the molecular basis of successful implantation and pregnancy of the human embryo to improve IVF success

Grant Amount:

$666,000

Significance:

Failed implantation is a major factor limiting IVF success, even for euploid embryos. However, what is required at the molecular level for successful implantation of the human embryo remains largely unknown. In this proposal, we aim to identify lineage-specific factors and cell-cell interactions most closely associated with the earliest stages of implantation development in humans using single-cell RNAseq and bioinformatic approaches. In parallel, we are working develop a stem-cell based, in vitro model of the human embryo that recapitulates the earliest stages of implantation to rigorously test the role of candidate factors and interactions identified in the embryo. Together, these integrated models have the potential to provide much needed insight into the molecular mechanisms required for successful implantation and to focus advances in embryo culture and embryo selection to improve infertility treatment for our patients.

I cannot express enough how grateful I am to the ASRM Research Institute for grant funding for this project. One of the greatest motivating factors throughout my training and career is to improve IVF success by advancing our understanding of the molecular mechanisms required for the earliest stages of human development. However, it is extremely difficult to obtain funding for this research as it is not supported by federal funding. In fact, the ASRM Research Institute is one of the only sources of funding for these projects, and the work we are doing would absolutely not be possible without it. The Institute’s commitment to fill this gap is invaluable to provide the support needed to make the next advances in care for our patients and to support the careers of scientists and physicians dedicated to performing this research.

Heidi Cook-Andersen, MD, PhD
Assistant Professor
Reproductive Medicine and Biological Sciences
University of California, San Diego

Grant Project Title:

Establishment and characterization of miscarriage-specific human trophoblast stem cells

Grant Amount:

$40,000

Significance:

750,000 to 1,000,000 miscarriages happen in the United States annually. For couples who experience pregnancy loss, the cause is usually cytogenetic in 60% of cases, such as trisomy and monosomy. However, the cause of the remaining euploid miscarriages is usually not found. Therefore, there is a significant need for more studies to investigate new causes of human pregnancy loss, especially recurrent miscarriages, where 50% of couples will not find a cause. To elucidate the molecular mechanisms of miscarriages in humans, new tools are necessary to study these events as up until now; one significant barrier is the limited amount of tissue, mainly chorionic villi, available for analysis. Prior studies on early human placentation have primarily relied on transformed trophoblast cell lines or primary human trophoblast cells purified from the early placenta, which cannot be propagated. Therefore, a proliferating primary trophoblast cell culture system to study human miscarriage is an essential technical advancement to overcome these past research barriers. Recently, researchers have established control human trophoblast stem (TS) cell lines from first-trimester chorionic villi from normal pregnancies and human blastocysts from IVF. Therefore, our project aims to establish human TS cells from first-trimester miscarriage chorionic villi as a new tool to elucidate the pathophysiology of unexplained first-trimester miscarriages and ultimately find new causes of recurrent miscarriages.

This ASRM Research Institute grant has been instrumental in providing me with the essential funds to carry out the necessary pilot experiments required to establish the feasibility of this high-risk, high-reward research project. Furthermore, the data generated from this grant has provided the crucial scientific support and feasibility data required to submit a competitive R01 grant and to help me towards my long-term career goal to be an independent physician-scientist. It is hard to express in a few words how grateful I am to ASRM Research institute for providing this grant to me as it allows me to ‘stay in the research game’ and one day translate my bench research to help couples with recurrent miscarriages.

Winifred Mak, MD, PhD
Associate Professor, UT Health Sciences at San Antonio and Dell Medical School (UT Austin)

Grant Project Title:

Human Embryo Mosaicism: Towards Understanding Longitudinal and Developmental Genetic Concordance Between Embryonic Trophectoderm, Inner Cell Mass, and Stem Cells

Grant Amount:

$666,000

Significance:

Our hypothesis is that blastocyst regional cell genetic concordance is low, embryonic mitotic segregation errors are frequent, and that collectively, these biological factors contribute to embryonic mosaicism and limitations in predicting offspring genetic normalcy. This hypothesis is being addressed with two specific aims: 1) to elucidate regional genetic concordance/discordance within human preimplantation blastocysts trophectoderm, inner cell mass, and resulting human embryonic stem cells with single cell-sequencing; and 2) to quantify the incidence of age-related human oocyte/embryo meiotic and mitotic nondisjunctions as they contribute to blastocyst mosaicism.

These studies represent first-in-field approaches to systematically and longitudinally identify developmental and genetic events in human embryos that must be understood to allow confidence in preimplantation genetic testing-aneuploidy (PGT-A) use and interpretations. These data will guide the future of PGT-A and have an immediate impact of eliminating knowledge-gaps in PGT-A, mosaicism, and decision-making for reproductive healthcare providers, patients, and the general population.

Gary D. Smith, Ph.D., H.C.L.D.
Professor of Ob/Gyn, Physiology, and Urology
Director of MStem Cell Lab
Director of Reproductive Sciences Program
University of Michigan

Grant Project Title:

Identification of transcriptomic and epigenetic coordinates for post-implantation human embryonic development

Grant Amount:

$666,000

Significance:

Post-implantation human embryonic development beyond the blastocyst stage is pertinent to a variety of disorders in human reproduction such as implantation failure, fetal defects, placental insufficiencies and early pregnancy loss. However, our knowledge of cell-lineage decisions in the post-implantation human embryo remains severely limited and there is a critical need to explore the molecular control underlying the formation of trophoblast, epiblast and hypoblast lineages and the events surrounding implantation and gastrulation. In addition, it remains one of the premier goals of reproductive medicine to identify effective biomarkers that predict successful post-implantation development and pregnancy following uterine transfer of in-vitro fertilization (IVF) embryos. Our long-term goal is to understand cellular differentiation in the post-implantation human embryo at the molecular level and develop novel genomic predictors of pregnancy outcomes for pre-implantation testing of IVF embryos. This project aims to delineate the transcriptomic and epigenomic changes underlying human post-implantation lineage development and use this dataset to develop transcriptional and epigenetic predictors of successful implantation and gastrulation using a human post-implantation model in vitro.

We are immensely grateful to the ASRM Research Institute for supporting this project. It is very difficult to obtain funding for this line of research because the NIH currently restricts research projects involving reproductive medicine. As such, the ASRM Research Institute plays an important and unique role in funding basic research in human embryology and this support will unlock the tremendous translational potential in this field going forward. In our case it allows us to use cutting edge single cell multiome sequencing technology to address a fundamental question in reproductive biology – what are the molecular building blocks of a successful post-implantation human embryo and how can these single cell genomic technologies be used to identify high implantation potential embryos prior to uterine transfer?

Werner Neuhausser, MD PhD
Instructor in Obstetrics, Gynecology and Reproductive Biology
Division of Reproductive Endocrinology & Infertility
Beth Israel Deaconess Medical Center
Harvard Medical School

---

Grant Project Title:

Characterizing Fertility Concerns among Women in Academic Medicine and Evaluating the Economic Impact of Fertility Preservation for Deferred Reproduction

Grant Amount:

$50,000

Significance:

Although women are more likely than men to pursue a career in academic medicine, they also tend to leave academic medicine, reduce their work hours, or reroute their careers during their childbearing years. In addition, many female physicians delay childbearing, and studies have documented higher rates of infertility, obstetric complications, and childlessness in female physicians relative to the general population. Female physicians report high levels of interest in fertility preservation and assisted reproduction technology (ART) options. Two primary factors that may prevent women in academic medicine from undergoing oocyte vitrification at younger ages (≤ 35 years old) include a lack of awareness regarding the importance of age on the efficiency and success of fertility preservation and the high costs of fertility preservation without adequate insurance coverage. The purpose of this project was to investigate and characterize the unique fertility concerns of women in academic medicine and examine female physicians’ understanding of the role of age in determining the efficiency and success of fertility preservation options.

The ASRM research institute grant was instrumental in beginning my work to explore the challenges faced by women in medicine with regard to fertility and family building concerns. The literature has shown a large degree of gender disparity in academic promotion and rank and the theme of fertility and family building and how that has been a contributing factor has previously not been explored. This grant allowed me to do some foundational research upon which I hope to build and really helped to get this project off the ground. I am tremendously appreciative of the support from ASRM in this work.

Eve Feinberg, MD
Associate Professor of OB/GYN, specializing in REI at Northwestern University

 Click bottom right to view full screen

---

Grant Project Title:

Novel, Noncoding-RNA-Mediated Mechanisms for Regulation of Follicular Quantity and Quality

Grant Amount:

$50,000

Significance:

Reproductive health issues as serious as miscarriage, birth defects, and the loss of fertility due to advancing age or exposure to gonadotoxic agents can frequently be traced back to a decline in oocyte quality and/or quantity. Dr. Kallen's studies have the potential to define noncoding RNAs as major regulators of ovarian reserve and are directly related to the NIH Fertility and Infertility Branch’s mission of supporting research that enhances our understanding of normal reproduction and reproductive pathophysiology.

The importance of the ASRM research grant in my career development cannot be overstated. The ASRM grant, which came at a time when I needed bridge funds to “stay in the game” as an REI physician-scientist transitioning to independence, paved the way for me to successfully obtain independent NIH funding. My ASRM funding allowed me to complete ongoing studies, continue building on preliminary data, and successfully respond to critiques from prior R01 submissions. The culmination of these ASRM-supported efforts was an R01 submission which was scored at the first percentile! This work, and this achievement, would simply not have been possible without ASRM’s support, and I am so incredibly grateful for the resources, support, and demonstrated commitment to young physician-scientists by this incredible organization.

Amanda N. Kallen, MD
Associate Professor, Yale Medicine
Division of Reproductive Endocrinology & Infertility
Department of Obstetrics, Gynecology, & Reproductive Sciences