Daniel MacPhee

• B.Sc.(Hons.) PEI
• Ph.D. Western Ontario

Research Programs:

The Importance of the Chaperome in Uterine Smooth Muscle Function during Pregnancy

The uterus is a female organ that houses the developing fetus during pregnancy. This organ contains a smooth muscle layer named the myometrium and during pregnancy it goes through a program of differentiation and adaptation to physiological stress marked by changes in the muscle cells at the molecular and cellular level. The consequence of this programming is the production of a tissue that can generate precisely coordinated and powerful contractions (labour) to ensure the timely delivery of a term fetus with sufficiently mature organ systems for survival outside the uterus. When the myometrium is not programmed properly, it can contribute to a significantly increased risk of preterm birth, which accounts for 75% of all infant deaths during pregnancy. Yet we cannot resolve conditions such as preterm birth unless we have a greater understanding of how the myometrium develops and adapts during normal pregnancy in the first place.

The Chaperome is a collection of proteins that assist in maintaining normal cell function by regulating the health of cellular proteins and helping cells adapt to acute and chronic stress. Small stress or heat shock B family (HSPB) proteins are chaperome members and are also able to promote immunological balance in cells and tissues. The MacPhee lab examines whether HSPB proteins can modulate uterine smooth muscle cell inflammation, promote production of their internal skeleton (the cytoskeleton) during inflammation, and if these stress proteins are necessary for myometrial cells to produce chemical messengers known as cytokines. Furthermore, since the uterus undergoes fetal-induced stretch during pregnancy and HSPB proteins are induced by such biophysical forces, we are investigating whether HSPB proteins can mediate myometrial cell stretch induced activation of key transcriptional co­activators, which respond to mechanical forces. We have also recently discovered that myometrial cells producing “courier packages” named extracellular vesicles, and we are examining whether stretch forces stimulate vesicle production and release, the loading of chaperome cargo within these packages, and whether inflammation­induced vesicles can act as communication devices between uterine cells.

Funded by NSERC – 2023-2028

The Importance of the Chaperome in Human Placental Development

The placenta is a life sustaining bridge between mother and fetus that possesses many functions such as producing hormones, regulating oxygen and carbon dioxide exchange, and enabling nutrition of the fetus. Proper placental development is crucial for the health of the baby and mother as diseases/conditions during pregnancy such as preeclampsia and fetal growth restriction can result from improper development. These conditions are also linked to an increased risk of diseases in the future adult such as cardiovascular disease, since fetal programming is now considered integral to developmental origins of health and disease. We are investigating whether chaperome members contribute to human placental development. By studying this process, we will contribute the building blocks of knowledge that will lead to production of more effective predictors of conditions/diseases of pregnancy related to improper placental development, better therapeutic strategies to tackle them, and improved healthcare outcomes for future Canadians.

COLLABORATIONS:

The MacPhee lab is also collaborating with colleagues on many projects including examination of Porcine Reproductive and Respiratory Syndrome Virus-2 infection and movement across the pig maternal-fetal interface.  More information on this and other projects can be found on the website of the Swine Health Research Group: https://research-groups.usask.ca/swinehealth/#AdvancingSwineHealth

SIGNIFICANCE TO SASKATCHEWAN

The MacPhee lab is part of the One Reproductive Health Group. The research training undertaken by students in the laboratory fosters production of the next generation of scientists or highly qualified people for careers in the province. Trainees are encouraged to be curious, learn how to plan experiments, analyze and interpret their research findings, and discuss their research findings with other scientists and the general public. Many trainees gain the knowledge and experiences required for future careers in medicine, veterinary medicine, biotechnology fields, industrial or interdisciplinary research-related activities within Saskatchewan and across Canada. If you would like to join the MacPhee research team, please contact Dr. MacPhee by email at d.macphee@usask.ca. Applications are invited from all qualified candidates with interests in reproductive sciences. For additional information on the One Reproductive Health Group please visit http://www.usask.ca/groups/onereproductivehealth/.

 Selected Recent Publications (Trainees and PI in bold, *designates corresponding author):

Welsh, JA, Goberdhan, DCI, O’Driscoll, L, Buzas, EI, Blenkiron, C, Bussolati, B, Cai, H, Di Vizio, D, Driedonks, TAP, Erdbrügger, U, Falcon-Perez, JM, Fu, Q-L, Hill, AF, Lenassi, M, Lim, SK, Mahoney, MG, Mohanty, S, Möller, A, Nieuwland, R, … Witwer, KW. (2024). Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advancd approaches. Journal of Extracellular Vesicles, 13: e12404. https://doi.org/10.1002/jev2.12404

Miskiewicz EI, Olaloku A, MacPhee, BK, *MacPhee DJ. (2023). Phosphoserine-86-HSPB1 (pS86-HSPB1) is cytoplasmic and highly induced in rat myometrium at labour. Histochemistry and Cell Biology. 159: 149–162. DOI: 10.1007/s00418-022-02158-1.

Barrera-Zarate J, Detmer SE, Pasternak JA, Hamonic G, MacPhee DJ, Harding JCS. (2022). Detection of PRRSV-2 alone and co-localized with CD163 positive macrophages in porcine placental areolae. Veterinary Immunology and Immunopathology. 250: 110457. DOI: 10.1016/j.vetimm.2022.110457.

Kawamura E, Hamilton GB, Miskiewicz EI, *MacPhee DJ. (2021). Examination of FERMT1 expression in placental chorionic villi and its role in trophoblast invasion. Histochemistry and Cell Biology. https://doi.org/10.1007/s00418-021-01977-y.

Russell MF, Bailey GC, Miskiewicz EI, *MacPhee DJ. (2021). HSPA1A is Markedly Expressed in Rat Myometrium by Labour and Secreted via Myometrial Cell-Derived Extracellular Vesicles. Reproduction, Fertility and Development. 33: 279-290. https://doi.org/10.1071/RD20242.

Van Goor, A, Pasternak, JA, Walker, K, Hong, L, Malgarin, C, MacPhee, DJ, Harding, JCS, *Lunney, JK. (2020). Differential responses in placenta and fetal thymus at 12 days post infection elucidate mechanisms of viral level and fetal compromise following PRRSV2 infection. BMC Genomics. 21: 763. doi: 10.1186/s12864-020-07154-0.

Awang-Junaidi, AH, Fayaz, MA, Kawamura, E, Sobchishin, L, MacPhee, DJ, *Honaramooz, A. (2020). Live-cell imaging and ultrastructural analysis reveal remarkable features of cultured porcine gonocytes. Cell and Tissue Research 381: 361–377. doi: 10.1007/s00441-020-03218-5.

Pasternak JA, MacPhee, DJ, *Harding, JCS. (2020). Maternal and Fetal Thyroid Dysfunction following Porcine Reproductive and Respiratory Syndrome Virus2 infection. Veterinary Research. Veterinary Research 51: 47. https://doi.org/10.1186/s13567-020-00772-2.

Pasternak, JA, MacPhee, DJ, *Harding, JCS. (2020). Fetal Cytokine Response to Porcine Reproductive and Respiratory Syndrome Virus-2 infection. Cytokine 126: 154883. https://doi.org/10.1016/j.cyto.2019.154883.

Suleman, M, Malgarin, CM, Detmer, SE, Harding, JCS, *MacPhee, DJ. (2019). The porcine trophoblast cell line PTr2 is susceptible to porcine reproductive and respiratory syndrome virus-2 infection. Placenta 88: 44–51. https://doi.org/10.1016/j.placenta.2019.10.004.

Bhatti, M, Dinn, S, Miskiewicz, EI, *MacPhee, DJ. (2019). Expression of Heat Shock Factor 1, Heat Shock Protein 90 and Associated Signaling Proteins in Pregnant Rat Myometrium: Implications for Myometrial Proliferation. Reproductive Biology 19: 374–385. https://doi.org/10.1016/j.repbio.2019.09.003.

Kawamura E, Hamilton GB, Miskiewicz EI, *MacPhee DJ. (2018). FERMT2 is highly expressed in human placental villi and modulates trophoblast invasion. BMC Developmental Biology, 18:19. doi.org/10.1186/s12861-018-0178-0.

Suleman M, Novakovic P, Malgarin CM, Detmer SE, Harding JCS, *MacPhee DJ. (2018). Spatiotemporal immunofluorescent evaluation of porcine reproductive and respiratory syndrome virus transmission across the maternal-fetal interface. Pathogens and Disease, 76(5): 1-14. doi:10.1093/femspd/fty060.