Modeling the human bone marrow niche in vivo

Area 7: Biology of malaria and other vector-borne diseases
Modeling the human bone marrow niche in vivo and its role in malaria
Paolo Bianco
Department of Molecular Medicine
: 0039 06 4997 3377 - @:[email protected]
This proposal is inscribed in our group’s long standing interest in the BM niche (biology
and disease). We will refine and fully characterize functionally our system for heterotopic
transplantation of skeletal progenitors, which results in the establishment of a BM niche in
immunocompromised mice. This will involve in situ characterization and functional probing
of the capacity of the niche to host blood borne human hematopoietic progenitor/stem cells
and cancer cells as a probe of niche promiscuity. We will then attempt and develop
innovative models of the interaction between malaria gametocytes and human BM. To this
end, we will use a) immunocompromised mice, to analyze the bulk biodistribution of
infused human RBCs infected with immature and mature gametocytes; b) mice carrying
human bone marrow stroma in heterrotopic organoids; c) mice carrying human blood
vessels in heterotopic organoids; c) humanized immunocompromised mice with human
erythropoiesis, BM stroma, and/or blood vessels. This studies will address, in addition to
the biology of the human HSC niche in vivo, its emerging potential key role as a relais in
the human-to-mosquito parasite transmission and survival of in a broad ecosystem.
Studies on malaria are planned as a collaboration with the group of Dr Pietro Alano at ISS.
Dr Alano is a world recognized leader in malaria biology. Funding granted will contribute to
the costs of the human stem cell biology/modeling work; work directly related to genetic
manipulation and analysis of the P. falciparum gametocytes will be separately covered by
funding in Dr Alano’s group.
Relevant publications:
Sacchetti, B., Funari, A., Michienzi, S., Di Cesare, S., Piersanti, S., Saggio, I., Tagliafico, E., Ferrari, S., Robey,
P.G., Riminucci, M., Bianco, P.. (2007). Self-renewing osteoprogenitors in bone marrow sinusoids can
organize a hematopoietic microenvironment. Cell 131, 324-336.
Bianco, P. (2011). Bone and the hematopoietic niche: a tale of two stem cells. Blood 117, 5281-5288.
Bianco, P. (2013). Don't market stem-cell products ahead of proof. Nature 499, 255.
Bianco, P. (2014). "Mesenchymal" Stem Cells. Annual Review of Cell and Developmental Biology. 30:677704
Bianco, P., Barker, R., Brustle, O., Cattaneo, E., Clevers, H., Daley, G.Q., De Luca, M., Goldstein, L., Lindvall,
O., Mummery, C., et al. (2013a). Regulation of stem cell therapies under attack in Europe: for whom the
bell tolls. The EMBO journal 32, 1489-1495.
Bianco, P., Cao, X., Frenette, P.S., Mao, J.J., Robey, P.G., Simmons, P.J., and Wang, C.Y. (2013b). The
meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine.
Nature medicine 19, 35-42.
Bianco, P., Robey, P.G., and Simmons, P.J. (2008). Mesenchymal stem cells: revisiting history, concepts, and
assays. Cell Stem Cell 2, 313-319.
Bianco, P., and Sipp, D. (2014). Regulation: Sell help not hope. Nature 510, 336-337.
Serafini, M., Sacchetti, B., Pievani, A., Redaelli, D., Remoli, C., Biondi, A., Riminucci, M., and Bianco, P.
(2014). Establishment of bone marrow and hematopoietic niches in vivo by reversion of chondrocyte
differentiation of human bone marrow stromal cells. Stem cell research 12, 659-672.
Piersanti, S., Remoli, C., Saggio, I., Funari, A., Michienzi, S., Sacchetti, B., Robey, P.G., Riminucci, M., and
Bianco, P. (2010). Transfer, analysis, and reversion of the fibrous dysplasia cellular phenotype in human
skeletal progenitors. Journal of bone and mineral research : the official journal of the American Society for
Bone and Mineral Research 25, 1103-1116.
Saggio, I., Remoli, C., Spica, E., Cersosimo, S., Sacchetti, B., Robey, P.G., Holmbeck, K., Cumano, A., Boyde,
A., Bianco, P., RIminucci, M. (2014). Constitutive Expression of Gsalpha in Mice Produces a Heritable, Direct
Replica of Human Fibrous Dysplasia Bone Pathology and Demonstrates Its Natural History. Journal of Bone
and Mineral Research 29:2357-2368
Remoli, C., Michienzi, S., Sacchetti, B., Di Consiglio, A., Cersosimo, S., Spica, E., Robey, P.G., Holmbeck, K.,
Cumano, A., Boyde, A., Davis, G., Saggio, I., Riminucci, M., Bianco, P. (2014). Osteoblast-specific expression
of the Fibrous Dysplasia (FD) causing mutation, Gsalpha produces a high bone mass phenotype but does
not reproduce FD in the mouse. Journal of Bone and Mineral Research. Dec 8 DOI 10.1002/jbmr.2425
Balakumaran, A., Mishra, P.J., Pawelczyk, E., Yoshizawa, S., Sworder, B.J., Cherman, N., Kuznetsov, S.A.,
Bianco, P., Giri, N., Savage, S.A., merlino, G., Dumitriu, B., Dunbar, C.E., Young, N.S., Alter, B.P., Robey, P.G.
(2014). Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology
disorders. Blood. Dec 12 DOI 10.1182/blood-2014-06-566810
Kassem, M., and Bianco, P. (2015). Skeletal stem cells in space and time. Cell 160, 17-19.
Research Group
Mara Riminucci, Associate Professor
Alessandro Corsi, Assistant Professor
Benedetto Sacchetti, Researcher
Cristina Remoli, Post-doctoral fellow
Rossella Labella; Samantha Donsante PhD students
Emanuela Spica, Technician
Biagio Palmisano, Student
Collaborators
Dr Pietro Alano at ISS – Istituto Superiore di Sanità