Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell–deficient tgε26 Mice

Abstract

A large, transient population of natural killer (NK) cells appears in the murine uterine mesometrial triangle during pregnancy. Depletion of uterine (u) NK cells, recently achieved using gene-ablated and transgenic mice, results in pathology. Pregnancies from matings of homozygous NK and T cell–deficient tgε26 mice have <1% of normal uNK cell frequency, no development of an implantation site–associated metrial gland, and an edematous decidua with vascular pathology that includes abnormally high vessel walls/lumens ratios. Fetal loss of 64% occurs midgestation and placentae are small. None of these features are seen in pregnant T cell–deficient mice. To confirm the role of the NK cell deficiency in these reproductive deficits, transplantation of tgε26 females was undertaken using bone marrow from B and T cell–deficient scid/scid donors. Engrafted pregnant females have restoration of the uNK cell population, induced metrial gland differentiation, reduced anomalies in the decidua and decidual blood vessels, increased placental sizes, and restoration of fetal viability at all gestational days studied (days 10, 12, and 14). Thus, uNK cells appear to have critical functions in pregnancy that promote decidual health, the appropriate vascularization of implantation sites, and placental size.

A Study of Reproductive Performance in Pregnant, IL-2 Receptor .BETA.-chain Overexpressed Transgenic Mice.

“…However, the detailed function of uNK cells remains to be fully defined. In tgε26 mice (T -/B + /NK -), abrupt abortion in midpregnancy resulted from reduction of the placenta and abnormalities of the structure of blood vessels in the decidua basalis [2][3][4]. This account was confirmed by the use of tgε26 mice reconstituted with the bone marrow of scid/scid mice (T -/B -/NK + ).…”

“…This account was confirmed by the use of tgε26 mice reconstituted with the bone marrow of scid/scid mice (T -/B -/NK + ). NK-reconstituted tgε26 mice showed the retrieval of uNK cells, the differentiation of metrial gland, the decrease in abnormalities of blood vessels in the decidua, the increase in placental weight, and the recovery of fetal viability in mid-pregnancy (10, 12 and 14 days) [4]. Therefore, uNK cells are bone marrow-derived, and have crucial roles in the formation of placenta, the fetal development through the regenesis and modification of blood vessel architecture.…”

Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice

“…Unexpectedly, defective spiral arterial development and modification were found in normoglycemic NOD and NOD.scid mice. This pathology is absent in implantation sites of pregnant scid mice, which lack T-and B-cells (36). NOD.scid mice have similar NK cell defects to NOD mice but do not develop insulitis or diabetes.…”

Genetic Deletion of Placenta Growth Factor in Mice Alters Uterine NK Cells

“…14 -17). Furthermore, in mice lacking uNK cells, the endometrial/maternal spiral arteries feeding into developing placentae (PL) do not undergo normally expected, pregnancy-associated changes in structure (18). IFN-␥ treatment of pregnant alymphoid mice induces appropriate arterial modification, suggesting that this uNK cell product has essential roles in endometrial support of PL (19).…”