Project Grant R01HD112424

DYSREGULATION OF ENDOMETRIAL INVASIBILITY PROXIMAL TO UTERINE SCAR AS A MECHANISM OF PLACENTA ACCRETA - ABSTRACT PLACENTA ACCRETA IS A SERIOUS MATERNAL CONDITION AFFECTING MORE THAN 1 IN 300 WOMEN IN THE US, AND RAPIDLY INCREASING IN FREQUENCY. ACCRETA IS CHARACTERIZED BY THE PLACENTA INVADING TOO DEEPLY INTO THE UTERUS, NECESSITATING HYSTERECTOMY UPON PARTURITION. THE MAJOR CORRELATE OF ACCRETA (OR INCRETA, OR PERCRETA) IS THE PRESENCE OF PREVIOUS UTERINE SCAR, MOSTLY DUE TO CAESARIAN SURGERY, ALTHOUGH THE DISEASE COULD MANIFEST WITHOUT PREVIOUS SCARS. VERY LITTLE IS UNDERSTOOD ABOUT THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THIS DISEASE, LEAVING LIMITED THERAPEUTIC AVENUES TO PURSUE. OUR OVERALL HYPOTHESIS STATES THAT WHILE NORMAL PLACENTAL INVASION IS PREDICATED ON A FINE BALANCE OF PRO- AND ANTI-INVASABLE SIGNALING AT THE MATERNAL-FETAL INTERFACE, PLACENTA ACCRETA IS A RESPONSE OF SCAR INDUCED DYSREGULATION IN THIS SIGNALING, LEADING TO EXCESSIVE AND UN- CONTROLLED INVASION. SPECIFICALLY, WE POSIT THAT THE DYSREGULATED BIOMECHANICAL MICROENVIRONMENT AT THE SCAR TRANSFORMS DECIDUAL FIBROBLASTS INTO AN INFLAMMATORY STATE, PRODUCING CHEMOATTRACTIVE CYTOKINES RECRUITING EXTRAVILLOUS TROPHOBLASTS TOWARDS THE SCAR. WE HAVE DEVELOPED A FRAMEWORK TERMED ELI (EVOLVED LEVELS OF INVASABILITY) THAT EXPLAINS THE HIGHLY INVASIVE NATURE OF PLACENTATION IN CERTAIN MAMMALS AS PRIMARILY A STROMAL CHARACTERISTIC. BASED ON ELI FRAMEWORK, AND OUR PRELIMINARY FINDINGS, WE POSIT THAT ABERRANT MATRIX CUES FROM SCAR DYSREGULATE DECIDUAL DEFENSE, RESULTING IN UNCONTROLLED TROPHOBLAST INVASION LEADING TO ACCRETA. USING A BIOENGINEERED MODEL OF SCAR DECIDUA (HIGH RIGIDITY, HIGH COLLAGEN DENSITY, ANISOTROPIC NANOTOPOGRAPHY), WE OBSERVED DYSREGULATED MECHANORESPONSIVE SIGNALING IN DECIDUAL FIBROBLASTS (DESFS), RESULTING IN CHEMOTACTIC RECRUITMENT OF EXTRAVILLOUS TROPHOBLASTS (EVTS) TOWARDS SCAR, AS WELL AS PROMOTING EVT INVASION BY ALTERED DESF CONTRACTILITY. SPECIFICALLY, SCAR RESULTS IN HIGH ACTIVATION OF PROTEIN KINASE C BY PIEZO-1 MECHANOSENSITIVE CA2+ CHANNEL. INCREASED PKC ACTIVATION PHOSPHORYLATES NFKB, A MASTER REGULATOR OF INFLAMMATORY RESPONSE, RESULTING IN PRODUCTION OF IL-8 AND G-CSF, POTENT CHEMOATTRACTANTS FOR EVTS. IN THIS PROPOSAL, WE WILL ELUCIDATE THE MISSING LINKS IN THESE MECHANISMS USING A COMBINATION OF SPATIALLY DEFINED EXPLORATION AT TRANSCRIPTIONAL, MOLECULAR AND TISSUE LEVEL SCALES. WE HAVE DEVELOPED MANY TECHNOLOGICAL PLATFORMS SPECIFICALLY FOR UNDERSTANDING STROMAL INVASION OF TROPHOBLASTS: A MODEL OF SCAR DECIDUA THAT RECAPITULATES ACCRETA PHENOTYPE, A NANO-FABRICATED PLATFORM FOR QUANTIFICATION OF STROMAL INVASION, CELLULAR FORCE MEASUREMENT AT EVT-DESF INTERFACE, AND A MICROFLUIDIC PLATFORM TO MEASURE PARACRINE CROSS-TALK BETWEEN EVTS AND DESFS. AS ACCRETA IS A SPATIALLY DEFINED PATHOLOGY, WE WILL USE SPATIAL TRANSCRIPTOMICS IN HUMAN ACCRETA SAMPLES TO IDENTIFY CHANGES IN DECIDUAL STATE PROXIMAL TO SCAR. FINALLY, WE WILL PROFILE, AND ESTABLISH THE CAUSALITY OF PARACRINE CROSS-TALK BETWEEN DESFS AND EVTS IN ACCRETA MANIFESTATION. THIS INTEGRATED STUDY COMBINING SYSTEMS AND MECHANISTIC APPROACHES WILL SHED LIGHT TO ELUCIDATE THE BIOLOGY OF SCAR INDUCED UNCONTROLLED PLACENTAL INVASION, AND IDENTIFY TARGETS TO THERAPEUTICALLY LIMIT ACCRETA PATHOGENESIS.