Key Takeaways & Executive Findings
- •• Genetically modified MSCs secreting SCF, TPO, FLT3L, and IL3 support HSPC expansion without exogenous cytokines, preserving stemness and multilineage potential. • The biomimetic feeder layer reduces culture-induced stress and improves outcomes for HDR-mediated gene editing, particularly for fetal hemoglobin reactivation. • This approach offers a cost-effective alternative to traditional cytokine supplementation, potentially lowering the overall cost of HSPC gene therapy. • The engineered MSCs closely mimic the bone marrow niche, enhancing the therapeutic value of HSPCs for gene therapy applications.
Abstract
Background: Hematopoietic Stem and Progenitor Cells (HSPCs) gene therapy has shown significant progress, with commercial approval for at least four distinct haematological disorders, and poised for a rapid expansion in the upcoming years. Despite these advancements, the ex vivo culture of HSPCs continues to present significant challenges. The stress induced by ex vivo culture can negatively impact transplantation outcomes, while the need for exogenous cytokine supplementation contributes to the high costs associated with gene therapy products. Methods: We developed genetically modified human bone marrow MSCs (GM-MSCs) secreting cytokines such as Stem cell factor (SCF), Thrombopoietin (TPO), FMS-like tyrosine kinase-3-ligand (FLT3L), and Interleukin-3 (IL3), closely resembling bone marrow cellular niche to augment HSPCs culture. Results: HSPCs proliferate on GM-MSCs akin to standard conditions, devoid of external cytokine supplementation and these HSPCs retain their stem cell characteristics, colony-forming potential, stemness gene signatures, and capacity for long-term multilineage reconstitution in NBSGW mice. We demonstrate that our biomimetic feeder layer supports and alleviates stress associated with Homology Directed Repair (HDR) mediated gene-editing of HSPCs for fetal haemoglobin reactivation for a potential application in β-hemoglobinopathies gene therapy. Conclusion: Our GM-MSCs offer a compelling alternative to traditional cytokine supplementation by establishing a biomimetic bone marrow niche that fosters HSPC expansion while maintaining their stemness. These findings underscore the potential of engineered MSCs to revolutionize ex vivo HSPCs culture, ultimately enhancing their therapeutic value for gene therapy applications.
1. Introduction
Over the past decade, hematopoietic stem and progenitor cells (HSPCs) gene therapy has made remarkable progress, driven by the advancement of cutting-edge technologies and methodologies that enhance its safety and precision [1]. The approval of Casgevy, the first CRISPR/Cas9-based HSPCs gene therapy for sickle cell disease (SCD), marks a significant milestone [2]. HSPCs possess a unique ability to be mobilized from the bone marrow, undergo ex vivo manipulation, and successfully re-engraft, where they self-renew and differentiate into all hematopoietic lineages. This remarkable versatility positions HSPCs gene therapy at the forefront of ex vivo genetic engineering approaches.
Despite its potential, ex vivo manipulation of HSPCs remains challenging. Key obstacles include culture-induced cellular stress, cytotoxic effects from the manipulation process, reduced engraftment efficiency of modified cells, and the presence of a large fraction of committed progenitors in the graft, which can lower the in vivo frequency of gene-modified cells in the long term [3, 4]. These limitations necessitates the retrieval and manipulation of large quantities of HSPCs from patients, which increases the overall cost of the production process [5, 6]. Additionally, the requirement for various manipulation reagents and cytokines from commercial vendors further complicates the logistics and expense associated with HSPCs gene therapy.
The stem cell niche in human bone marrow provides essential scaffolds, cellular frameworks, and soluble cues that support the maintenance of HSPCs. Mesenchymal stromal cells (MSCs) play a critical role in maintaining HSPCs homeostasis primarily through the release of paracrine factors and also through HSPC-MSC contact, which collectively foster a supportive environment for haematopoiesis [7, 8]. Several pre-clinical and clinical studies have highlighted the significant role of MSCs when cocultured or co-transplanted with adult HSPCs or umbilical cord blood (UCB) HSPCs. This approach has been shown to enhance engraftment, accelerate hematopoietic recovery, and effectively mitigate the risk of graft-versus-host disease (GvHD) [9–15].
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Sevanthy Suresh, Vigneshwaran Venkatesan, Manoj Kumar K. Azhagiri, Gokulnath Mahalingam, Prathibha Babu Chandraprabha, Mohankumar K. Murugesan, Sanjay Kumar, Saravanabhavan Thangavel, Srujan Marepally (2026). Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04474-4
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Frequently Asked Questions
What is the main challenge in ex vivo culture of HSPCs?
The main challenges include culture-induced cellular stress, cytotoxic effects, reduced engraftment efficiency, and the high cost of exogenous cytokine supplementation.
How do genetically modified MSCs support HSPC expansion?
Genetically modified MSCs secrete key cytokines such as SCF, TPO, FLT3L, and IL3, mimicking the bone marrow niche and supporting HSPC expansion without external cytokine supplementation.
What are the benefits of using GM-MSCs over traditional cytokine supplementation?
GM-MSCs provide a biomimetic niche that reduces culture stress, maintains stemness, and lowers costs by eliminating the need for expensive recombinant cytokines.
Can this approach be applied to gene editing of HSPCs?
Yes, the biomimetic feeder layer alleviates stress associated with HDR-mediated gene editing, as demonstrated for fetal hemoglobin reactivation in β-hemoglobinopathies.
What is the significance of this study for HSPC gene therapy?
This study offers a cost-effective and efficient alternative for ex vivo HSPC culture, potentially improving the scalability and accessibility of gene therapy for hematological disorders.
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