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Abstract
Development of lymphoid tissue is determined by interactions between stromal lymphoid tissue organiser (LTo) and hematopoietic lymphoid tissue inducer (LTi) cells. A failure for LTo to receive appropriate activating signals during embryogenesis through lymphotoxin engagement leads to a complete cessation of lymph node (LN) and Peyer’s patch development, identifying LTo as a key stromal population for lymphoid tissue organogenesis. However, little is known about the equivalent stromal cells that induce spleen development. Here, by dissociating neonatal murine spleen stromal tissue for re-aggregation and transplant into adult mouse recipients, we have identified a MAdCAM-1+CD31+CD201+ spleen stromal organizer cell-type critical for new tissue formation. This finding provides an insight into the regulation of post-natal spleen tissue organogenesis, and could be exploited in the development of spleen regenerative therapies.
Highlights
Development of lymphoid tissue is determined by interactions between stromal lymphoid tissue organiser (LTo) and hematopoietic lymphoid tissue inducer (LTi) cells
Since artificial lymph nodes have been previously synthesized using stromal cells loaded onto a collagen sponge[16], we assessed whether D3 neonatal spleen cell-loaded sponges would sustain tissue formation, alongside control aggregate-sheet constructs and non-scaffold supported aggregates (Fig. 1C)
Inflammatory stimuli required for artificial lymph nodes (aLN) synthesis through enforced stromal lymphotoxin expression and addition of activated DC16 appear unnecessary factors for spleen regeneration, a reflection of secondary rather than tertiary lymphoid organogenesis
Summary
Development of lymphoid tissue is determined by interactions between stromal lymphoid tissue organiser (LTo) and hematopoietic lymphoid tissue inducer (LTi) cells. By dissociating neonatal murine spleen stromal tissue for re-aggregation and transplant into adult mouse recipients, we have identified a MAdCAM1+CD31+CD201+ spleen stromal organizer cell-type critical for new tissue formation This finding provides an insight into the regulation of post-natal spleen tissue organogenesis, and could be exploited in the development of spleen regenerative therapies. The capacity for spleen to filter blood means that pathogens or antigens entering the marginal zone (MZ) are effectively screened, enabling immediate innate or longer-lasting adaptive immune responses This is facilitated by numerous immune cell types including macrophages[2], monocytes[3], dendritic cells (DC)[4] and T and B cells located in the MZ, red pulp (RP) and white pulp (WP). The equivalent stromal cells directing spleen development, remain unknown Identification of such spleen organizer cells would be essential in designing specific strategies for spleen tissue regeneration. We describe a murine model for spleen cell-aggregate graft transplantation, and report the isolation of a defined spleen stromal population that is essential for regeneration of neonatal spleen tissue
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