Contribution of fetal microchimeric cells to maternal wound healing in sickle cell ulcers

Abstract

Leg ulcers are a major complication of sickle cell disease (SCD) that can cause severe complications. They are particularly challenging to treat and therapeutic innovation is needed. We previously showed that SCD ulcers display a delayed wound healing due to decreased angiogenesis. During pregnancy, fetal microchimeric cells (FMC) transferred to the mothers are recruited to maternal wounds and improve angiogenesis. After delivery, FMC persist in maternal bone marrow for decades. Here, we questioned whether fetal cells could also improve SCD ulcers in the post-partum setting. We found that skin healing was similarly improved in post-partum mice and in pregnant mice, through increased proliferation and angiogenesis. In a SCD mouse model that recapitulates SCD refractory ulcers, we showed that post-partum SCD mice healed more quickly as compared to virgin ones. This was associated with the recruitment of fetal cells in maternal wounds where they harbored markers of leukocytes and endothelial cells. In a retrospective cohort of SCD patients, we demonstrated using several parameters that ever parous SCD women had a decreased burden related to leg ulcers compared to nulliparous women. Taken together, these results indicate that healing capacities of FMC are maintained long after delivery and may be targeted to promote wound healing in post-partum SCD patients.

Fetal microchimerism and beyond: a new player in regenerative medicine

“…El Hoss et al have demonstrated that fetal haemoglobin, produced by fetal haemoglobin-containing cells (F-cells), decreases ineffective erythropoiesis 9 by playing an antiapoptotic role in terminal erythroid differentiation. In the present study, the authors demonstrated that fetal cells display features of hematopoietic progenitor cells by the high expression of genes associated with hematopoietic stem cells, such as Sca1 and Myc 5 .…”

“…These fetal cells can differentiate into leukocytes and endothelial cells, thus contributing to the healing of the ulcers. This is not surprising since amniotic fluid stem cells can accelerate wound healing by enhancing reepithelialization and reducing scarring 5 . It has previously been shown, by some of the same authors, that the ccl2/ccr2 signalling is responsible for the recruitment of fetal cells in maternal wound healing 6 .…”

“…In their article, Alkobtawi et al 5 demonstrated that these cells are functional, in vivo, and contribute to healing ulcers in a disease setting, such as Sickle Cell Disease (SCD). Fetal microchimeric cells (low levels of fetal cells in maternal circulation) are potent contributors to maternal wound healing, even postnatally 5 . These fetal cells can differentiate into leukocytes and endothelial cells, thus contributing to the healing of the ulcers.…”

“…They can also be stored in a biobank for future use[Figure 1]. The study's findings can be expanded to other skin conditions, such as epidermolysis bullosa 5 . In a clinical trial, infusion of allogeneic fetal cord mesenchymal stem cells was found to be safe and had transient clinical benefits in patients with epidermolysis bullosa 8 .…”

“…Some commercial biobanks offer isolation and storage of placental stem cells, but the latter is of high cost and has yet to be widely used 7 . Since the mother is tolerant to her semi-allogenic fetus, infusion of expanded fetal stem cells from her baby isolated at delivery, should be tolerated with an even more remarkable healing effect 5 . This could be the beginning of a Phase I clinical trial following the publication from Alkobtawi et al Various ways of targeting the site of ulceration could be addressed.…”