Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.

Froebel, J.; Rahmig, S.; Metz, J.; Kucinski, I.; Svensson, C.-M.; Reinhardt, S.; Salbach-Hirsch, J.; Coppin, E.; Mende, N.; Henning, N.; Percin, G. I.; Weschenfelder, F.; Koehler, A.; Platz, A.; Gottgens, B.; Rauner, M.; Figge, M. T.; Hoefer, T.; Dahl, A.; Waskow, C.

doi:10.64898/2026.04.30.719914

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bioRxiv · 10.64898/2026.04.30.719914

Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.

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Abstract

The regulation of human hematopoietic stem cell (HSC) function within its native bone marrow microenvironment remains poorly understood due to the limitations of existing humanized models. Here, we present a non-conditioned human HSC xenotransplantation platform that serves as a physiologically relevant in vivo surrogate to study these complex cellular interactions. Using this system, we uncover a dynamic, cross-species communication between human HSCs and the murine niche, revealing a profound cellular and molecular plasticity of the bone marrow microenvironment in response to humanization. Upon engraftment, platelet-derived growth factor receptor alpha positive (Pdgfra+) mesenchymal stromal cells (MSCs) undergo significant numerical expansion and a major transcriptional shift, transitioning from a mixed adipo- and osteo-primed state toward a leptin receptor positive (Lepr+) predominantly adipo-primed, hematopoiesis-supporting signature. Functional validation demonstrates that this niche plasticity is a critical determinant of stem cell engraftment: the targeted depletion of Lepr+ MSCs or the genetic deletion of stem cell factor results in the rapid mobilization and lack of engraftment of human HSCs, respectively. Our findings establish niche plasticity as a primary regulator of human HSC function and demonstrate the utility of this cross-species platform as a modular genetic toolbox for precise in vivo engineering of the bone marrow microenvironment. Ultimately, this adaptable system provides a powerful framework for elucidating human stem cell biology and advancing bone marrow transplantation therapies.

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Froebel, J., Rahmig, S., Metz, J., Kucinski, I., Svensson, C.-M., Reinhardt, S., Salbach-Hirsch, J., Coppin, E., Mende, N., Henning, N., Percin, G. I., Weschenfelder, F., Koehler, A., Platz, A., Gottgens, B., Rauner, M., Figge, M. T., Hoefer, T., Dahl, A., Waskow, C.. 2026-05-04. Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.. https://doi.org/10.64898/2026.04.30.719914

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