Systemic administration of bone marrow‐derived cells leads to better uterine engraftment than use of uterine‐derived cells or local injection

Abstract

Stem cells are recruited to the uterus where they differentiate into endometrial cells and have been suggested as potential therapy for uterine injury such as Asherman's syndrome. However, it is unknown whether local intrauterine injection may result in better stem cell engraftment of the uterus compared with systemic administration, and whether uterine‐derived cells (UDCs) may confer an advantage over BM‐derived cells (BMDCs). Mice underwent local injury to a single uterine horn. Green fluorescent protein (GFP)‐expressing BMDCs, UDCs or saline (control) were injected either intravenously or locally (uterine lumen) into wild‐type recipients. Two or 3 weeks post‐transplant, uterine tissues were collected for fluorescence‐activated cell sorting (FACS) and immunohistochemistry/immunofluorescence studies. Mice injected intravenously with BMDCs or UDCs had increased GFP+ cells recruitment to the non‐injured or injured uterus compared to those injected locally. No significant differences were noted in GFP+ cell recruitment to the injured versus non‐injured horn. In addition, systemic injection of BMDCs led to greater recruitment of GFP+ cells at 2 weeks and 3 weeks compared with UDCs. Immunohistochemical staining demonstrated that GFP+ cells were found in stroma but not in epithelium or blood vessels. Immunofluorescence analysis revealed that GFP+ cells were mostly CD45‐negative, and negative for CD31 and cytokeratin, confirming their stromal identity. In conclusion, the systemic route of administration results in better recruitment of BMDCs or UDCs to the injured uterus than local injection. In addition, BMDCs recruitment to the uterus is greater than UDCs. These findings inform the development of stem cell‐based therapies targeting the uterus.

Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy

“…Determining the ideal routes of administration for various DMD therapies have proven to be a challenge [11,12]. Though there is scarce literature comparing routes of stem cell administration in the mdx mice for treatment of DMD cardiomyopathy, studies using a murine model for Ashermann's syndrome have shown systemic administration of bonemarrow derived stem cells led to better stem cell engraftment in uterus, leading to improved fertility when compared with local intrauterine injection [53]. Based on our experience, with the systemic-intraosseous injection of bone marrow cells and chimeric cells showing better engraftment and maintenance of the donor derived chimerism [43,45,46], in this study, we focused on systemic administration of DEC through intraosseous injection, as this facilitates the process of systemic delivery and potential engraftment to other muscles including the cardiac muscle as confirmed in this study by increased dystrophin expression and reduced fibrosis which correlated with significant improvement of EF and FS on echocardiography.…”

Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus

“…A certain degree of overlap may exist in both cell populations, and in situ fate determination of CD44 + cells by lineage tracing will reveal whether they can self-renew and differentiate into the complete uterine epithelial lineage as these uterine epithelial stem cells do. In addition to these proposed resident cell sources, the exogenous supply of bone marrow cells, through tissue transplantation from a donor animal, has led to the suggestion that bone marrow cells are able to contribute to uterine regeneration (12,36). Whether or not the conditions experienced by the uterus during tissue transplantation reflect physiological conditions will be critical in determining if such an exogenous cellular supply plays a role in supporting normal cyclical uterine regeneration, which the current study is focused on.…”

“…Nor is it clear whether such phenotypic characteristics would be seen in uterine stem cells. In vitro clonogenicity assays and transplantation have also been applied to search for potential uterine stem cells (2,(11)(12)(13), but evidence is lacking that the in vivo counterparts of these candidate cells behave like stem or progenitor cells. Mapping of the fate determination of these claimed stem or progenitor cell candidates during normal uterine cycling is required to define their stem cell potential.…”

Bone marrow-derived stem cells contribute to regeneration of the endometrium

“…The human endometrium is a dynamic remodeling tissue that undergoes over 400 cycles of growth, differentiation, and shedding of endometrial cells during the reproductive period [ 1 2 ]. This physiology is mainly regulated by the effects of sex steroid hormones and other biological molecules, and is essential for implantation and pregnancy in mammals.…”