Poster Presentation 2018 Hunter Cell Biology Meeting

Cis-dimerised junctional adhesion molecule A (cdJAM-A) is a critical regulator of HSC homing and maintenance in the niche (#102)

Benjamin Cao 1 2 , Christina Hart 3 , Sabine Iberl 3 , Gunnar Müller 3 , Brenda Williams 1 2 , Shen Y Heazlewood 1 2 , Andrew Vinson 1 2 , Xuan Sun 1 2 , Melanie Domingues 1 2 , Songhui Li 1 2 , Chad K Heazlewood 1 2 , David N Haylock 1 2 , Jochen Grassinger 3 , Susie Nilsson 1 2
  1. CSIRO, Clayton, VIC, Australia
  2. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  3. Department of Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany

The success of clinical haematopoietic stem cell (HSC) transplants is highly dependent on the ability of HSC to home to bone marrow (BM): a process that is relatively poorly understood. Although it is appreciated that haematopoietic recovery post-transplant is correlated to the number of infused HSC, greater understanding of homing mechanisms should lead to improved transplant strategies that are not solely reliant on the number of infused HSC. Herein, we demonstrate the cis-dimerised form of junctional adhesion molecule A (cdJAM-A) is highly expressed on murine and human BM HSC and its inhibition significantly impairs homing and engraftment of HSC and progenitors in murine transplant models. Importantly, cdJAM-A was demonstrated to maintain HSC quiescence in the BM niche as injection of anti-cdJAM-A blocking antibody induced significant and preferential expansion of murine BM HSC. Furthermore, treatment of mice with the clinical mobilisation agent granulocyte colony stimulating factor (G-CSF) resulted in significant reduction of cdJAM-A expression on murine HSC as a result of JAM-A cleavage by tumour necrosis factor α-converting enzyme (TACE; also known as ADAM metallopeptidase domain 17), which we demonstrate to be upregulated in BM. G-CSF treatment was also associated with reduced expression of CXCR4 as well as α4β1 and α9β1 integrin expression on BM progenitors, which together contributes to their mobilisation. Peripheral blood progenitors mobilised using G-CSF also have reduced expression of cdJAM-A, α4β1, α9β1 and CXCR4, which resulted in significantly reduced homing efficiency post-transplant when compared to progenitors mobilised using the α4β1/α9β1 integrin and CXCR4 antagonists, BOP and AMD3100, respectively. Consequently, we show that a single injection of BOP in combination with AMD3100 for 1 hour was capable of mobilising HSC and progenitors that had significantly greater long-term multi-lineage engraftment potential compared to a 4-day G-CSF approach. Together, our results identify cdJAM-A as a critical regulator of HSC trafficking and maintenance in the niche and suggests mobilisation strategies that do not abrogate cdJAM-A expression or function should result in improved clinical HSC transplants.