About

Milan K. Bagchi is the Deborah Paul Professor and Director of the School of Molecular and Cellular Biology at the University of Illinois. He holds professorships in Molecular and Integrative Physiology as well as Biomedical and Translational Sciences. Dr. Bagchi's educational background includes a B.S. and M.S. from the University of Calcutta, India, a Ph.D. from the University of Nebraska, and postdoctoral training at Baylor College of Medicine in Houston, TX. His research focuses on steroid hormone signaling mechanisms in normal physiology and diseases, particularly the roles of estrogen and progesterone in regulating gene networks that control reproduction and early development. His laboratory aims to identify molecular pathways regulated by these steroid hormones during the growth and differentiation of hormone-responsive tissues, with a special emphasis on embryo implantation and fertility. The physiological effects of estrogen and progesterone are mediated through nuclear receptors that act as ligand-inducible transcription factors, and Dr. Bagchi's work characterizes these hormonal mechanisms at molecular and cellular levels. His research hypothesizes that defects in critical hormonal signaling pathways lead to improper uterine function during implantation, resulting in pregnancy loss and infertility. Using gene expression profiling combined with ChIP-sequencing analyses, his lab has uncovered novel steroid-regulated pathways that provide important insights into the cellular mechanisms controlling implantation. Functional analyses in gene knockout mouse models further elucidate the molecular networks mediating hormonal regulation of this process. A clear understanding of the gene pathways underlying tissue-specific actions of estrogen and progesterone receptors is expected to aid in developing targeted therapeutic strategies for hormone-dependent cancers such as breast, ovarian, and endometrial cancers, as well as disease conditions like endometriosis and infertility.

Research topics

• Biology
• Endocrinology
• Genetics
• Cell biology
• Physiology
• Cancer research
• Internal medicine
• Medicine
• Chemistry
• Bioinformatics
• Immunology
• Andrology

Selected publications

• Deciphering the maternal uterine signals that shape placenta development

  Reproduction · 2026-05-01

  articleSenior author

  In brief: Proper placental development depends not only on fetal trophoblast signaling but also on critical maternal uterine signals. This review highlights how decidual factors and maternal-fetal crosstalk regulate trophoblast invasion and placentation. Abstract: In humans and rodents, proper formation of a hemochorial placenta is essential for a successful pregnancy, as the placenta serves as the maternal-fetal interface that facilitates the exchange of nutrients, gases, and waste between the mother and the developing fetus. The fetal compartment of the placenta is formed by extraembryonic trophoblast cells that proliferate and differentiate into distinct lineages that play specialized roles during placental development. Trophoblast lineage development and function are highly dependent upon embryonic paracrine signaling and timely activation of transcription factors within the trophoblasts. However, recent studies have increasingly emphasized the critical role of maternal factors in regulating trophoblast differentiation and placental development. Notably, conditional knockout mouse models have demonstrated the essential contribution of maternal decidual expression of specific molecular signals in orchestrating these processes. In this review, we summarize the role of maternal uterine signals in shaping placental development. We examine the role of decidua-derived secreted factors in directing trophoblast lineage specification and promoting appropriate levels of trophoblast invasion. Additionally, we explore the crosstalk between maternal- and fetal-derived signals that collectively regulate the extent and timing of trophoblast invasion into the uterine tissue. The interplay between maternal immune cells and trophoblasts is also discussed, with a focus on mechanisms that not only support immune tolerance to the semi-allogeneic placenta but also mediate trophoblast invasion and vascular remodeling. Finally, we consider the clinical implications of maternal influences on placentation, including the emerging potential of decidual extracellular vesicles as non-invasive biomarkers for pregnancy health and placental dysfunction.

  PublisherDOI

• Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling

  Endocrinology · 2025-08-29 · 1 citations

  articleOpen accessSenior author

  During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor runt-related transcription factor 1 (RUNX1) in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrate that RUNX1 regulates the conserved hypoxia-inducible factor 2 α-RAB27B pathway in primary human endometrial stromal cells (HESCs) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including angiopoietin-related protein 2 (ANGPTL2) and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

  PublisherOA PDFDOI

• Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-14 · 1 citations

  preprintOpen accessSenior author

  During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor RUNX1 in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrated that RUNX1 regulates the conserved HIF2α-RAB27B pathway in primary human endometrial stromal cells (HESC) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including ANGPTL2 and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

  PublisherOA PDFDOI

• Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice

  Toxicological Sciences · 2025-05-05 · 4 citations

  articleOpen access

  Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. Although past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed chronically to a mixture of phthalates for 12 mo through ad libitum chow consumption. Our studies revealed that continuous exposure to this phthalate mixture led to uterine hyperplasia with a significant increase in gland-to-stroma ratio. Endometrial hyperplasia is commonly caused by heightened estrogenic action and inflammatory response in the uterus, leading to increased proliferation of endometrial epithelial cells. Indeed, we observed a marked upregulation of several known estrogen-regulated genes, proinflammatory chemokines, elevated homing of macrophages, and increased KI67 staining in the endometrial epithelial cells upon phthalate exposure. Several signaling pathways, including the MAPK/ERK and Wnt/β-Catenin pathways, promote cell proliferation, leading to the hyperproliferative state of the endometrial cells. Our studies revealed no alteration of the MAPK/ERK pathway but a marked enhancement of the Wnt/β-Catenin signaling pathway in phthalate-exposed uteri. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.

  PublisherOA PDFDOI

• Phthalates Impair Estrogenic Regulation of HIF2α and Extracellular Vesicle Secretion by Human Endometrial Stromal Cells

  Endocrinology · 2025-04-22 · 3 citations

  articleOpen accessSenior author

  High levels of exposure to di(2-ethylhexyl) phthalate (DEHP), a known endocrine disruptor, have been linked to adverse pregnancy outcomes, yet the mechanisms by which it impacts human uterine functions remain unclear. Here we report that exposure of differentiating primary human endometrial stromal cells (HESCs) to an environmentally relevant concentration of DEHP or its primary metabolite, mono(2-ethylhexyl) phthalate, markedly reduces the expression of the estrogen-regulated transcription factor hypoxia-inducible factor 2-α (HIF2α). We also noticed a simultaneous decrease in RAB27B expression, which is crucial for the trafficking and secretion of extracellular vesicles (EVs). EVs enhance communication among various cell types within the pregnant uterus, thereby ensuring reproductive success. We found that estrogen receptor α (ERα) could no longer bind to the HIF2α regulatory region following phthalate treatment, and epigenetic analysis suggested that this may be due to hypermethylation of nearby CpG islands. Further investigation revealed a potential interaction between ERα and the transcription factor specificity protein 1 (Sp1) within the HIF2α regulatory region, which is affected by the inhibition of Sp1 binding to the phthalate-induced hypermethylated DNA. Additionally, our results suggest that the abnormal DNA methylation is likely due to increased expression of the DNA methyltransferase 1 (DNMT1) gene in response to phthalate exposure. Overall, this study provides valuable mechanistic insights into how phthalate-induced differential DNA methylation disrupts estrogenic regulation of the HIF2α gene and, consequently, EV secretion during HESC differentiation. This knowledge is essential for understanding how phthalates may lead to adverse reproductive outcomes by disrupting hormonal regulation of cell-to-cell communication in the uterus.

  PublisherOA PDFDOI

• Phthalates Impair Estrogenic Regulation of HIF2α and Extracellular Vesicle Secretion by Human Endometrial Stromal Cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-17

  preprintOpen accessSenior authorCorresponding

  Abstract Di(2-ethylhexyl) phthalate (DEHP), a known endocrine-disrupting chemical, is a plasticizer found in many common consumer products. High levels of DEHP exposure have been linked to adverse pregnancy outcomes, yet little is known about how it affects human uterine functions. We previously reported that the estrogen-regulated transcription factor hypoxia-inducible factor 2 alpha (HIF2α) promotes the expression of Rab27b, which controls the trafficking and secretion of extracellular vesicles (EVs). EVs facilitate communication between multiple cell types within the pregnant uterus, ensuring reproductive success. In this study, we report that exposure of differentiating primary human endometrial stromal cells (HESC) to an environmentally relevant concentration (1 μg/mL) of DEHP or its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) markedly reduces the expression of HIF2α . We also observed a concomitant decrease in RAB27B expression, reducing EV secretion from HESC. Interestingly, we found that DEHP or MEHP exposure disrupts estrogenic regulation of the HIF2α/Rab27b signaling pathway. Estrogen receptor alpha (ERα) could no longer bind to the HIF2α regulatory region following phthalate treatment, and epigenetic analysis suggested that this may be due to hypermethylation of nearby CpG islands. Further investigation revealed a potential interaction between ERα and the transcription factor Sp1 within the HIF2α regulatory region, which is affected by the inhibition of Sp1 binding to the phthalate-induced hypermethylated DNA. Additionally, our results suggest that the abnormal DNA methylation is likely due to increased expression of the DNA methyltransferase 1 ( DNMT1 ) gene in response to phthalate exposure. Overall, this study provides valuable mechanistic insights into how phthalate-induced differential DNA methylation disrupts estrogenic regulation of the HIF2α gene and, consequently, EV secretion during HESC differentiation. This knowledge is crucial for our understanding of how phthalates may cause adverse reproductive outcomes by disrupting the hormonal regulation of cell-to-cell communication within the pregnant uterus.

  PublisherOA PDFDOI

• Uterus: Growth Factors and Cytokines

  Elsevier eBooks · 2024-07-07

  book-chapter
  PublisherDOI

• Progesterone Signaling in the Endometrium

  Elsevier eBooks · 2024-07-14

  book-chapterSenior author
  PublisherDOI

• Maternal–fetal mechanisms underlying adaptation to hypoxia during early pregnancy

  Trends in Endocrinology and Metabolism · 2024-07-29 · 12 citations

  reviewSenior author
  PublisherDOI

• Long-term dietary exposure to a mixture of phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-20

  preprintOpen access

  Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. While past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed to a phthalate mixture for 6 and 12 months through ad libitum chow consumption. We previously reported that continuous exposure to this phthalate mixture for 6 months led to uterine fibrosis. In this study, we show that the exposure, when continued beyond 6 months to 1 year, caused fibrotic uteri to display hyperplasia with a significant increase in gland to stroma ratio. Endometrial hyperplasia is commonly caused by unopposed estrogen action, which promotes increased expression of pro-inflammatory cytokines and chemokines and proliferation of the endometrial epithelial cells. Indeed, RNA sequencing analysis revealed a marked upregulation of several estrogen-regulated genes, Wnt ligands that are involved in oncogenic pathways, as well as chemokines, in phthalate-exposed uterine tissues. Consequently, the exposed uteri exhibited increased proliferation of endometrial epithelial cells, and a heightened inflammatory response indicated by extensive homing of macrophages. Further studies revealed a marked enhancement of the Wnt/β-Catenin signaling pathway, potentially contributing to the development of endometrial hyperplasia. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.

  PublisherOA PDFDOI

Recent grants

• Role of Hypoxia in Regulating Stromal-Epithelial Communication during Pregnancy

  NIH · $1.6M · 2018–2024

• NIH Grant U54HD013541

  NIH · $14.9M · 2003

• NIH Grant U54HD055787

  NIH · $13.4M · 2014

• NIH Grant R21HD078983

  NIH · $431k · 2017

• NIH Grant R01HD044611

  NIH · $1.2M · 2008

Frequent coauthors

• Indrani C. Bagchi

  University of Illinois Urbana-Champaign

  179 shared

• Quanxi Li

  Gansu Agricultural University

  45 shared

• Robert N. Taylor

  Jacobs (United States)

  37 shared

• Athilakshmi Kannan

  37 shared

• Francesco J. DeMayo

  National Institute of Environmental Health Sciences

  35 shared

• Mary J. Laws

  University of Illinois Urbana-Champaign

  34 shared

• John P. Lydon

  Baylor College of Medicine

  30 shared

• M. Jeyakumar

  17 shared

Awards & honors

• Romano Professorial Scholar