The niche/microenvironment shapes the fate of researchers and stem cells
Beate Heissig, MD
Division of Stem Cell Dynamics Center of Stem Cell Biology and Regenerative Medicine
The Institute of Medical Science The University of Tokyo
Visiting Associate Professor
Principal Investigator
Current positions
Center for Stem Cell Biology and Regenerative Medicine
Division of Stem Cell Dynamics
The Institute of Medical Science
Juntendo University School of Medicine, Center for Atopy
-1984 High School, Germany
1984-1990 Aachen & Marburg University (School of Medicine)
1990 M.D. Marburg University School of Medicine, Germany
1994 M.D. National Bone Marrow Donor Center, Tuebingen
-1989 Physician, Tuebingen/Heidelberg University, Heidelberg
University Medical School
1989-2002 2 yrs Funding through German cancer society ; Post
doc and Senior Research Associate at Weill Medical College of
Cornell University, USA
2003 Funding through Humbolt Foundation/Germany (1yrs) and
the Leukemia/lymphoma society; post-doc at Juntendo University
2004 Assistant Prof. at Institute of Medical Science, The
University of Tokyo, Japan
2008-2010 Funding through a mentor-based program: Frontier
Research Initiative from MEXT)
2012 Associate Prof. at IMSUT, The University of Tokyo
Career path
Publications before arrival in Japan
These publication and the research funds I brought lead to a Post doc and one year later to an Assistant Prof. position in Japan in 2003.
Thanks to a mentor-based program from MEXT I became an Associate Professor in 2012.
Beate Heissig
Primary Salven P, et al. FASEB J. 16, 1471-3, 2002. Heissig B,* et al. Cell 109, 625-637, 2002. Heissig B,* et al. Nature Med. 8, 841-849, 2002. Rafii S, et al. Semin. Cell Dev. Biol. 13, 61-67, 2002. Sick C, et al. Ann. Hematol. 80, 9-16, 2001. Hattori K, et al. J. Exp. Med. 193,1005-1014, 2001. Hattori K, et al. Blood 97, 3354-3360, 2001. Moore MA, et al. Ann. N. Y. Acad. Sci. 938, 36-45, 2001. Dias S*, et al. PNAS 98, 10857-10862, 2001. Lyden D, et al. Nat. Med. 2001 Heissig B, et al. Leuk. Research 24, 217-31, 2000. Dias S, et al. J. Clin. Inv. 106, 511-521, 2000. Lane WJ, Dias S, et al. Blood 96, 4152-4159, 2000. Schultheis B, et al. Folia Biol. 46, 251-255, 2000.
Reviews Rafii S, et al. Nat. Rev. Cancer 2, 826-835, 2002. Rafii S, et al. Sem. Cell Dev. Biol. 13(1), 64-67, 2002. Wu Y, et al. Nature Medicine 7, 1194-201, 2001. Rafii S, et al. Gene Therapy 9, 631-641, 2002. Pasternak et al. Leukemia 13, Suppl. 1: S55-S64 (1999).
Niche
Architecture: a recessed space (to keep a picture, sculpture protected) Ecology: function or position of a species within an ecological community. A specie’s niche includes the physical environment to which it has become adapted and its role as producer and consumer of food resources
These days, we say that people have "found their niche" when they've found work they're good at and that they enjoy.
In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some) can generate bone, cartilage, fat, cells that support the formation of blood, fibrous connective tissue, and extracellular matrix.
Stem cells and their niche
Niche cells
Mesenchymal stem cells
From: Mark et al., Nat Rev. Imm 2008
Mesenchymal stem cells
ECM
Immune cells leukocytes
“Matrix is everywhere”: Extracellular matrix (ECM) In the body the extracellular matrix gives tissues their structural and mechanical properties The components of the matrix contribute to tissue specificity of cells
NICHE CELLS require proteases to migrate through extracellular matrix to modify growth factor signaling, and to modify cellular adhesion
Inflammation
Tissue regeneration
Stem cell expansion
Degradation
Inactivation
Activation
Change of receptor
specificity
Adhesion molecules
(e.g. VCAM-1)
BM matrix proteins
(e.g. laminin)
Cell receptors, ligands
(e.g. uPAR)
Cyto-/chemokine (KitL,
MCP-1, CXCL5)
The proteolytic niche
Mod from: Heissig ADDR, 2015
Proteases are enzymes that catalyze the breakdown of proteins by hydrolysis of
peptide bonds.
Extracellular matrix
Cancer growth
Lab focus
Hematopoiesis = blood cell generation Angiogenesis = blood vessel generation
Physiological: during wound healing, and tissue development. Pathological: during tissue regeneration, in diseases like atherosclerosis, hind limb ischemia, rheumatoid arthritis, diabetic retinopathy and cancer.
Proteases in the niche/microenvironment
Physiological: daily blood cell production, and tissue development. Pathological: blood cell regeneration after chemotherapy, in diseases like blood cell cancer (leukemia), and inflammation.
Current studies using various disease models to studying protease functions
Pro-MMP9
PlasminPlasminogen
tPA
Toluidine blueAlkaline phosphatase Oil Red O
Before dif. Adipo Osteo Chondro
cont
-MS
CtP
A-M
SC
Dahri et al. 2016 Blood Niche cell expansion
Ohki et al. Blood 2012 Tashiro et al. Blood 2015
Blood vessels for tissue regeneration and Stem cell maintenance
Hematopoietic stem cell expansion
Munakata, Gastroenterology 2015
1
Cancer
Protease +/+ and -/- mice
Ishihara et al.,
Leukemia 2012
2
TNF-a
Blood cell transplantation rejection (GvHD), inflammatory bowel disease
Sato, Leukemia 2015
Protease/PAI1 inhibitor
Surgery induced colon adhesion
Honjo, FASEB, in Revision
3 Inflammation
THE LAB NICHE
MATRIX Language
Technician Office personal Researcher within the institute or outside
Jap./foreign students
Funding
Niche inhabitants
PI if the lab
A niche can protect, but also isolate.
- When you leave your country of origin you leave the protective niche, where you know the support system (senior scientists/zenpai, knowledge on funding etc.).
- Arriving in a foreign country, you join a lab with the general expectation that you will return to your home country. So the PI usually does not feel mentorship responsibility (career development).
- If you made it and established a laboratory it is hard to recruit native (e.g. Japanese) students and technical stuff, because Japanese fear that they are not able to reenter the Japanese network system (researcher niche) to promote them after they leave the lab.
- Grant applications in Japan require more and more networking and support collaboration-based
science, which foreigners often do not have. As a foreigner you often attract foreign student, you grow up foreign researchers who return to their own countries. They will not feed back in your local support (zenpai) system that in the future helps you: e.g. as local collaborators.
Problems for foreigners to establish a functional niche
Suggestion: Individual development plan (IDP) based on mentorship
MENTORSHIP for Foreign researcher (post doc, senior scientist)
Foreign researcher
PROBLEM: No mentorship for foreigner researcher. Foreign researcher are regarded as migratory rather than permanent worker.
Foreign researcher
Foreign researcher
Foreign researcher
FUTURE PLAN
JOB OFFER: a technician with native Japanese skills (latest from 4/2017) a post doc position in case your salary is fully funded
SEEKING: collaborations with foreign researchers in various research fields to do joint
research and establish a network
Beate Heissig
E-mail: [email protected]
