Simple Approach to Increase Donor Hematopoietic Stem Cell Dose and Improve Engraftment in the Murine Model of Allogeneic In Utero Hematopoietic Cell Transplantation

Abstract

The rationale for in utero hematopoietic cell transplantation (IUHCT) rests on exploitation of normal events during hematopoietic and immunologic ontogeny to allow allogeneic hematopoietic engraftment without myeloablative conditioning. Host hematopoietic competition is among the primary barriers to engraftment in IUHCT. In the murine model this can be partially overcome by delivery of larger donor cell doses, but volume is limiting. Enrichment of donor hematopoietic stem cells (HSCs) would seem to offer a more efficient approach, but such enriched populations have engrafted poorly in existing models of IUHCT. To increase HSC dose while maintaining the presence of accessory cells, we used a less stringent enrichment protocol of single-step lineage depleted cells alone (lin-) or in combination with whole donor bone marrow mononuclear cells. Our results confirm that increasing doses of HSCs in combination with bone marrow accessory cells can dramatically improve engraftment after IUHCT. This represents a practical and clinically applicable strategy to maximize the engraftment potential of the donor graft without risk of treatment-associated toxicity.

Experimental and clinical progress of in utero hematopoietic cell transplantation therapy for congenital disorders

“…Studies from sheep model showed that engraftment after IUHCT was dose-dependent, which seemed to reach a plateau above the optimal dose (Zanjani et al, 1997). Moreover, Vrecenak et al (2020) demonstrated that increasing doses of Lin-cells combined with BM could dramatically improve both allogeneic early and late engraftment after IUHCT.…”

In Utero Gene Therapy for Primary Immunodeficiencies

“…Some potential strategies proposed have included RNA interferences, antibodies that target the fetal hematopoietic progenitors, targeted delivery of proapoptotic peptides to host stem cells, treatment of gene therapies with growth factors, 98 and adding enriched bone marrow to treatments. 99 PIDs have been at the forefront of many cutting-edge treatments, such as HSCT and postnatal gene therapies. While there are many barriers to overcome for prenatal gene therapy to be a safe and effective option for patients, it is very likely that one of the PIDs will be one of the first diseases cured by this technology.…”

“…Therefore, other strategies to improve engraftment are needed. Some potential strategies proposed have included RNA interferences, antibodies that target the fetal hematopoietic progenitors, targeted delivery of proapoptotic peptides to host stem cells, treatment of gene therapies with growth factors,98 and adding enriched bone marrow to treatments 99…”