"Challenges and Emerging Therapeutic Targets in Hematopoietic Cell Mobilization from Bone Marrow to Peripheral Blood"

Agata Szade^1*Gunsagar S Gulati^2*

• ¹Jagiellonian University, Kraków, Poland
• ²Dana–Farber Cancer Institute, Boston, Massachusetts, United States

In the early days of HCT, bone marrow biopsies were the sole source of hematopoietic stem cells (HSCs) for transplantation. While bone marrow harvests remain the preferred option for certain cases, such as pediatric transplants and non-malignant disorders, mobilized peripheral blood has become the primary source for approximately 90% of transplantations [1,4,5]. In this approach, donors receive mobilizing factors that stimulate the release of HSCs from the bone marrow into the bloodstream, making collection safer and more convenient. Umbilical cord blood (UBC)-derived hematopoietic stem and progenitor cells (HSPCs) are also used for some transplantations [1,5]. However, a key challenge with UCB-and sometimes mobilized blood-is obtaining a sufficient number of HSPCs [6][7][8]. Research is ongoing to develop methods to increase the number of mobilized cells in donors [9][10][11], reliably expand HSPCs ex vivo, and improve HSPC survival during and after transplantation.Two studies in this collection address these challenges. Li et al. describe the ex vivo expansion of UBC-derived HSCs using the small molecule chrysin, which delays HSC differentiation and inhibits apoptosis induced by reactive oxygen species (ROS). Prchal-Murphy, Zehenter, and colleagues report a strategy that combines existing drugs to enhance the survival of umbilical cord-derived HSPCs. Their work demonstrates that sequential priming of murine or human HSPCs with treprostinil and forskolin, followed by cinacalcet treatment in recipients, accelerates hematopoietic recovery and improves survival in transplanted mice.From the recipient's perspective, effective conditioning is crucial for proper engraftment of transplanted cells. Conditioning removes the patient's endogenous HSCs from their bone marrow niches, creating space for the donor's cells [12]. In cancer patients undergoing autologous HCT, conditioning is also needed to deplete residual cancer cells and minimize the risk of recurrence before transplanting isolated cells. This is typically achieved using chemotherapy, total body irradiation (TBI), or a combination of both. The choice of regimen depends on factors such as the type of disease, remission status, and patient-specific factors, such as age, comorbidities, organ function, prior treatments, and the risk of transplant-related complications [13]. Busulfan combined with cyclophosphamide is a commonly used myeloablative conditioning regimen in allogeneic HCT. [13,14]. However, Shi et al. report on a Phase I study evaluating the safety and efficacy of various myeloablative conditioning regimens, including busulfan, cyclophosphamide, cytarabine, and a purine nucleoside analog, cladribine, for autologous HCT in acute myeloid leukemia.For non-neoplastic diseases, non-genotoxic therapies are being explored for transplant conditioning, such as antibodies that block interactions between HSCs and their niches [15,16]. In cancer patients, however, conditioning also serves to eliminate tumor cells. While sub-lethal conditioning was historically considered optimal, studies have shown that the donor immune response against residual tumor cells-known as graft-versus-tumor (GVT) or graft-versusleukemia (GVL)-is critical in reducing recurrence risk [13,14]. Unfortunately, the immune reaction of donor cells against the recipient's tissues, termed graft-versus-host disease (GVHD), remains a serious complication of HCT [1,17]. Clinical data show that the risk of chronic GVHD is higher when transplanting mobilized blood compared to bone marrow aspirate [18][19][20]. To prevent and treat GVHD, various immunosuppressive drugs, primarily corticosteroids, are used. However, many patients develop steroid-refractory GVHD, which is challenging to treat [21]. New drugs are being investigated and introduced for this condition [22]. Among these, ruxolitinib-a JAK inhibitor originally approved for treatment of myelofibrosis-has shown promise. In this research topic, Zhang et al. explore its effectiveness in treating bronchiolitis obliterans syndrome (BOS), a pulmonary manifestation of GVHD. Another study by Liu et al. focuses on optimizing dosing and pharmacokinetics of tacrolimus, a calcineurin inhibitor, in pediatric HCT recipients.Hematopoietic cell transplantation is a constantly evolving field. As mobilized blood becomes the primary source of transplanted HSCs, it is crucial to enhance our understanding of GVHD mechanisms, the interplay between GVHD and GVT, and effective strategies for obtaining highquality, transplantable HSCs. While many questions remain unanswered, we hope this research topic will offer valuable new insights. BIBLIOGRAPHY: