Experimental hematology Lab Prof. Dr. C. Nombela Arrieta

Our lab is interested in studying how the heterogeneous constituents of mammalian bone marrow (BM) tissues are structurally and functionally interconnected to work as a single finely-tuned, sophisticated and versatile functional unit.

MSCA             CNA is funded by a Career Integration Grant of the Marie Sklodowska Curie Actions

SNSF CNA is a recipient of a project grant of the SNSF

Vontobel                         CNA has received a research project grant from the Vontobel Stifftung


Projects

César Nombela-Arrieta

Bone marrow microenvironment dynamics

Mammalian BM cavities contain highly dynamics tissues of unique functional and cellular complexity. Besides serving as principal hematopoietic sites during adulthood, BM tissues provide the necessary environment for the development of immune responses, and maintenance of immunological memory. The hematopoietic components of the BM are embedded within a highly complex stromal framework, which beyond lending more structural support, actively participates in the regulation of hematopoiesis. BM stromal constituents comprise dense microvascular networks, a hierarchically organized mesenchymal compartment and cells of neural origin. Our research program seeks to better dissect the cellular make-up of BM stroma, understand how stromal components assemble in unique spatial configurations and how they contribute to the regulation of BM hematopoietic and immunological function. Our goal is to ultimately how the BM structural integrity is fundamentally altered in pathological conditions, how this affects tissue organization and spezialized niche function, and the molecular and cellular mechanisms by which a fully competent/functional BM microarchitecture is regenerated post-injury.

For this purpose we employ advanced quantitative microscopy techniques that enable us to visualize, analyze and quantify the different cellular and non-cellular components found in large regions BM tissues in two and three-dimensions at subcellular resolution.

 

Hematopoietic Stem and Progenitor Cell niches

Hematopoietic stem and progenitor cells (HSPCs) are self-renewing, multipotent cells that sustain the continuous production of mature blood cells. HSPCs are thought to reside within the complex ecosystem of the BM in defined anatomical locations, termed niches, where they receive specific regulatory cues from neighboring cells, extracellular matriz and soluble proteins. Given the prominent role of HSPCs at the apex of the hematopoietic hierarchy, the precise description of HSPC niches in the BM is of critical importance to understand hematopoietic regulation and has major implications in regenerative medicine.

Using Laser Scanning Cytometry, we have recently provided a quantiative and comprehensive analysis of HSCP distribution in the BM and defined their interactions with both sinusoidal (venous equivalent of the BM) and arterial microvessels (Nombela-Arrieta et al, Nat Cell Biol. 2013 May; 15(5):533-43 see publications). We also employed this technology to analyze how localization in different BM regions regulated the hypoxic status of HSPCs.

One of the main goals of our research is to characterize how loss of HSPC functionality under certain pathologic conditions correlates with abnormalities in spatial distribution or loss of structural integrity of homeostatic HSPC niches.

Publications
2015

 
 

Kwak HJ, Liu P, Bajrami B, Xu Y, Park SY, Nombela Arrieta C, Mondal S, Sun Y, Zhu H, Chai L, Silberstein LE, Cheng T, Luo HR.
Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis.
Immunity. 2015 Jan 20;42(1):159-71.
Pubmed


 
 
2014

 
 

Gazit R, Mandal PK, Ebina W, Ben-Zvi A, Nombela-Arrieta C, Silberstein LE, Rossi DJ.
Fgd5 identifies hematopoietic stem cells in the murine bone marrow.
J Exp Med. 2014; June 30; 211(7):1315-31. Epub 2014 June 23.
Pubmed

2013

Liang OD, Lu J, Nombela-Arrieta C, Zhong J, Zhao L, Pivarnik G, Mondal S, Chai L, Silberstein LE, Luo HR.
Deficiency of lipid phosphatase SHIP enables long-term reconstitution of hematopoietic inductive bone marrow microenvironment.
Dev Cell. 2013 May 28;25(4):339-49.
Pubmed

Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chèvre R, A-Gonzalez N, Kunisaki Y, Zhang D, van Rooijen N, Silberstein LE, Weber C, Nagasawa T, Frenette PS, Castrillo A, Hidalgo A.
Rhythmic modulation of the hematopoietic niche through neutrophil clearance.
Cell. 2013 May 23;153(5):1025-35.
Pubmed

Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, Park SY, Lu J, Protopopov A, Silberstein LE.
Quantitative imaging of haematopoietic stem an progenitor cell localization and hypoxic status in the bone marrow microenvironment.
Nat Cell Biol.2013 May; 15(5):533-43. Epub 2013 Apr 28.
Erratum in: Nat Cell Biol. 2013; Aug 15(8):1016.
Pubmed

Staber PB, Zhang P, Ye M, Welner RS, Nombela-Arrieta C, Bach C, Kerenyi M, Bartholdy BA, Zhang H, Alberich-Jordà M, Lee S, Yang H, Ng F, Zhang J, Leddin M, Silberstein LE, Hoefler G, Orkin SH, Göttgens B, Rosenbauer F, Huang G, Tenen DG.
Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells.
Mol Cell. 2013 Mar 7;49(5):934-46. Epub 2013 Feb. 8.
Pubmed

Park SY, Wolfram P, Canty K, Harley B, Nombela-Arrieta C, Pivarnik G, Manis J, Beggs HE, Silbestein LE.
Focal adhesion kinase regulates the localization and retention of pro-B cells in bone marrow microenvironments.
J Immunol. 2013 Feb 1;190(3):1094-102. Epub 2012 Dec 21.
Pubmed

Amabile G, Welner RS, Nombela-Arrieta C, D'Alise AM, Di Ruscio A, Ebralidze AK, Kraytsberg Y, Ye M, Kocher O, Neuberg DS, Khrapko K, Silberstein LE, Tenen DG.
In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells.
Blood. 2013 Feb 21;121(8):1255-64. Epub 2012 Dec 4.
Pubmed

2012

Lu J, Sun Y, Nombela-Arrieta C, Du KP, Park SY, Chai L, Walkely C, Luo HR, Silberstein LE.
Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion.
Exp Hematol. 2012 Apr;40(4):307-17. Epub 2011 Dec 8.
Pubmed

2011

Nombela-Arrieta C, Ritz J, Silberstein LE.
The elusive nature and function of mesenchymal stem cells.
Nat Rev Mol Cell Biol. 2011 Feb;12(2):126-31.
Pubmed

2007

Nombela Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martinez-A C, Fukui Y, vn Andrian UH, Stein JV.
A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress.
J Exp Med. 2007 Mar 19; 2014(3):497-510. Epub 2007 Feb 26.
Pubmed

2006

Garcia-Bernal D, Sotillo-Mallo E, Nombela-Arrieta C, Samaniego R, Fukui Y, Stein JV, Teixido J.
DOCK2 is requierd for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin alpha4beta1.
J Immunol. 2006 Oct 15;177(8):5215-25.
Pubmed

2005

Stein JV, Nombela-Arrieta C.
Chemokine control of lymphocyte trafficking: a general overview.
Immunology. 2005 Sep;116(1):1-12.
Pubmed

Garcia-Bernal D, Wright N, Sotillo-Mallo E, Nombela-Arrieta C, Stein JV, Bustelo XR, Teixido J.
Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1.
Mol Biol Cell. 2005 Jul;16(7):3223-35. Epub 2005 May 4.
Pubmed

2004

Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, Marqués M, Carrera AC, Manes S, Fukui Y, Martinez-A C, Stein JV.
Differential requirements for DOCK2 and phosphoinositide-3-kinase gamm during T and B lymphocyte homing.
Immunity. 2004 Sep; 21(3):429-41.
Pubmed

2003

Stein JV, Soriano SF, M'rini C, Nombela-Arrieta C, de Buitrago GG, Rodriguez-Frade JM, Mellado M, Girard JP, Martinez-A C.
CCR7-mediated physiological lymphocyte homing involves activation of tyrosine kinase pathway.
Blood. 2003. Jan 1;101(1):38-44.
Pubmed