We identified a partially purified mesenchymal stem cell (MSC) population that maintains its multi-lineage potential both in vivo and in vitro. Most importantly, we demonstrated that as few as 500 purified cells can develop bone in vivo without prior cell expansion in culture. This prospective isolation process, based upon lessons learned from hematology, sets us apart from others in the mesenchymal biology field and will allow us to understand the crucial differences in stem cell properties between cell culture and in vivo environments. The overall objective of this application is to understand the biology of this stem cell population, including in vivo lineage progression, how they function in the stem cell niche and determine the functional relationships and crosstalk between HSCs and MSCs. The central hypothesis behind our proposed projects is that a true mesenchymal stem cell exists within the bone marrow and the activity of this stem cell, including interactions with HSCs, is dependent on its niche compartment. We plan to test our central hypothesis and accomplish our objectives by pursuing three specific aims.
Each aim offers the opportunity to generate new tools that will revolutionize the ability to discover and model the environmental factors that mediate cell function in complex in vivo systems such as the bone/bone marrow.
Aim 1. To identify and characterize cells within the bone marrow stroma that exhibit mesenchymal stem cell activity. We will answer the following compelling questions: 1) Do these purified cells function as stem cells in vivo? 2) What is the capacity of these purified cells to function in their native in vivo micro-environment? and 3) How do MSCs respond to physiologic stimuli? Aim 2. To identify the MSC niche and determine the extent to which the MSC pool and its niche changes under physiologic and pathologic conditions (Mapping and defining the niche). We will address the following experimental questions 1) Where do MSCs reside within the marrow? 2) Do MSC numbers change in response to physiologic and or pathologic stimuli, including a single dose of 5-FU, a single acute bleed and anabolic PTH treatment? 3) Do perturbations of the marrow alter/regulate the MSC phenotype? Aim 3. To determine the functional relationships and cross talk between HSCs and MSCs. 1) Do MSCs and HSCs co-localize to the same niche? 2) Do HSCs (isolated with SLAM family markers) regulate MSC fate?

Public Health Relevance

A fundamental question in cellular and developmental biology is how a stem cell niche develops, and how these niches support and maintain stem cell activity. We have pioneered the use of an in vivo model that we will now use to functionally characterize our prospectively isolated MSCs. Our projects are designed to understand the nature of these MSCs and how their microenvironment, including interactions with hematopoietic stem cells (HSCs), influences their biologic activity. The overall hypothesis driving our project is that a true mesenchymal stem cell exists within the bone marrow and the activity of this stem cell - including interactions with hematopoietic stem cells - is dependent on its niche compartment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082481-04
Application #
8300198
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Wright, Daniel G
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$360,857
Indirect Cost
$125,633
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sun, Hongli; Zhu, Feng; Hu, Qingang et al. (2014) Controlling stem cell-mediated bone regeneration through tailored mechanical properties of collagen scaffolds. Biomaterials 35:1176-84
Havens, Aaron M; Sun, Hongli; Shiozawa, Yusuke et al. (2014) Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo. Stem Cells Dev 23:689-701
Havens, Aaron M; Shiozawa, Yusuke; Jung, Younghun et al. (2013) Human very small embryonic-like cells generate skeletal structures, in vivo. Stem Cells Dev 22:622-30
Jung, Younghun; Kim, Jin Koo; Shiozawa, Yusuke et al. (2013) Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun 4:1795
Sun, Hongli; Kim, Jin Koo; Mortensen, Richard et al. (2013) Osteoblast-targeted suppression of PPAR? increases osteogenesis through activation of mTOR signaling. Stem Cells 31:2183-92
Taichman, Russell S; Parkinson, Joseph W; Nelson, Bonnie A et al. (2012) Leadership training for oral health professionals: a call to action. J Dent Educ 76:185-91
Taichman, Russell S; Parkinson, Joseph W; Nelson, Bonnie A et al. (2012) Program design considerations for leadership training for dental and dental hygiene students. J Dent Educ 76:192-9
McGee, S J; Havens, A M; Shiozawa, Y et al. (2012) Effects of erythropoietin on the bone microenvironment. Growth Factors 30:22-8
Kim, Jinkoo; Jung, Younghun; Sun, Hongli et al. (2012) Erythropoietin mediated bone formation is regulated by mTOR signaling. J Cell Biochem 113:220-8
Pedersen, Elisabeth A; Shiozawa, Yusuke; Mishra, Anjali et al. (2012) Structure and function of the solid tumor niche. Front Biosci (Schol Ed) 4:1-15

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