Matrix elasticity directs stem cell lineage specification.

doi:10.1016/J.CELL.2006.06.044

Home
/
Papers
/
Matrix elasticity directs stem cell lineage specification.

Journal Article•DOI•

Matrix elasticity directs stem cell lineage specification.

Adam J. Engler¹, Shamik Sen¹, H. Lee Sweeney¹, Dennis E. Discher•Institutions (1)

University of Pennsylvania¹

25 Aug 2006-Cell (Cell Press)-Vol. 126, Iss: 4, pp 677-689

TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.

read less

About: This article is published in Cell.The article was published on 2006-08-25 and is currently open access. It has received 12204 citations till now. The article focuses on the topics: Mesenchymal stem cell differentiation & Stem cell fate determination.

...read moreread less

Citations

PDF

Open Access

More filters

Journal Article•DOI•

Growth Factors, Matrices, and Forces Combine and Control Stem Cells

[...]

Dennis E. Discher¹, David J. Mooney², Peter W. Zandstra³•Institutions (3)

University of Pennsylvania¹, Harvard University², University of Toronto³

26 Jun 2009-Science

TL;DR: Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.

...read moreread less

Abstract: Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.

...read moreread less

2,446 citations

Journal Article•DOI•

The extracellular matrix: A dynamic niche in cancer progression

[...]

Pengfei Lu¹, Valerie M. Weaver², Zena Werb²•Institutions (2)

University of Manchester¹, University of California, San Francisco²

20 Feb 2012-Journal of Cell Biology

TL;DR: The extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties, is commonly deregulated and becomes disorganized in diseases such as cancer.

...read moreread less

Abstract: The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.

...read moreread less

2,353 citations

Journal Article•DOI•

Hydrogels in regenerative medicine

[...]

Brandon V. Slaughter¹, Shahana S. Khurshid¹, Omar Z. Fisher¹, Ali Khademhosseini², Nicholas A. Peppas¹ - Show less +1 more•Institutions (2)

University of Texas at Austin¹, Massachusetts Institute of Technology²

04 Sep 2009-Advanced Materials

TL;DR: The properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed.

...read moreread less

Abstract: Hydrogels, due to their unique biocompatibility, flexible methods of synthesis, range of constituents, and desirable physical characteristics, have been the material of choice for many applications in regenerative medicine. They can serve as scaffolds that provide structural integrity to tissue constructs, control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers between tissue and material surfaces. In this work, the properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed. Recent research involving several different hydrogels polymerized from a variety of synthetic and natural monomers using typical and novel synthetic methods are highlighted. Finally, special attention is given to the microfabrication techniques that are currently resulting in important advances in the field.

...read moreread less

2,339 citations

Journal Article•DOI•

Cell mechanics and the cytoskeleton

[...]

Daniel A. Fletcher¹, Daniel A. Fletcher², R. Dyche Mullins³•Institutions (3)

University of California, Berkeley¹, Lawrence Berkeley National Laboratory², University of California, San Francisco³

28 Jan 2010-Nature

TL;DR: An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

...read moreread less

Abstract: The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

...read moreread less

2,323 citations

Journal Article•DOI•

Environmental sensing through focal adhesions

[...]

Benjamin Geiger¹, Joachim P. Spatz², Alexander D. Bershadsky¹•Institutions (2)

Weizmann Institute of Science¹, Max Planck Society²

01 Jan 2009-Nature Reviews Molecular Cell Biology

TL;DR: The mechanisms of such environmental sensing are discussed, based on the finely tuned crosstalk between the assembly of one type of integrin-based adhesion complex, namely focal adhesions, and the forces that are at work in the associated cytoskeletal network owing to actin polymerization and actomyosin contraction.

...read moreread less

Abstract: Recent progress in the design and application of artificial cellular microenvironments and nanoenvironments has revealed the extraordinary ability of cells to adjust their cytoskeletal organization, and hence their shape and motility, to minute changes in their immediate surroundings. Integrin-based adhesion complexes, which are tightly associated with the actin cytoskeleton, comprise the cellular machinery that recognizes not only the biochemical diversity of the extracellular neighbourhood, but also its physical and topographical characteristics, such as pliability, dimensionality and ligand spacing. Here, we discuss the mechanisms of such environmental sensing, based on the finely tuned crosstalk between the assembly of one type of integrin-based adhesion complex, namely focal adhesions, and the forces that are at work in the associated cytoskeletal network owing to actin polymerization and actomyosin contraction.

...read moreread less

2,322 citations

1
2
3
4
5
…
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200

Collapse

References

PDF

Open Access

More filters

Journal Article•DOI•

Multilineage Potential of Adult Human Mesenchymal Stem Cells

[...]

Mark F. Pittenger, Alastair Morgan Mackay, Stephen C. Beck, Rama K. Jaiswal, Robin Douglas, Joseph D. Mosca, Mark Aaron Moorman, Donald William Jr. Ward Road Simonetti, Stewart Craig, Daniel R. Marshak¹ - Show less +6 more•Institutions (1)

Johns Hopkins University School of Medicine¹

02 Apr 1999-Science

TL;DR: Adult stem cells isolated from marrow aspirates of volunteer donors could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages.

...read moreread less

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

...read moreread less

20,479 citations

"Matrix elasticity directs stem cell..." refers background or methods in this paper

...…Sweeney,1 and Dennis E. Discher1,2,3,4,* 1Pennsylvania Muscle Institute 2School of Engineering and Applied Science 3Cell & Molecular Biology Graduate Group 4Physics Graduate Group University of Pennsylvania, Philadelphia, PA 19104, USA *Contact: discher@seas.upenn.edu DOI 10.1016/j.cell.2006.06.044...
[...]
...…specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell…...
[...]
...The myoblast induction media used here (MIM, Table S2) is already known to promote myogenesis, with expression of MyoD, Myogenin, and skeletal muscle myosin heavy chain (Gang et al., 2004; Pittenger et al., 1999)....
[...]
...Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissuelevel elasticity....
[...]
...…and have indeed been reported to differentiate into various anchorage-dependent cell types, including neurons, myoblasts, and osteoblasts (respectively, [Deng et al., 2005; Hofstetter et al., 2002; Kondo et al., 2005], [Pittenger et al., 1999], and [McBeath et al., 2004; Pittenger et al., 1999])....
[...]

Journal Article•DOI•

Tissue Cells Feel and Respond to the Stiffness of Their Substrate

[...]

Dennis E. Discher¹, Paul A. Janmey¹, Yu-li Wang²•Institutions (2)

University of Pennsylvania¹, University of Massachusetts Medical School²

18 Nov 2005-Science

TL;DR: An understanding of how tissue cells—including fibroblasts, myocytes, neurons, and other cell types—sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels with which elasticity can be tuned to approximate that of tissues.

...read moreread less

Abstract: Normal tissue cells are generally not viable when suspended in a fluid and are therefore said to be anchorage dependent. Such cells must adhere to a solid, but a solid can be as rigid as glass or softer than a baby's skin. The behavior of some cells on soft materials is characteristic of important phenotypes; for example, cell growth on soft agar gels is used to identify cancer cells. However, an understanding of how tissue cells-including fibroblasts, myocytes, neurons, and other cell types-sense matrix stiffness is just emerging with quantitative studies of cells adhering to gels (or to other cells) with which elasticity can be tuned to approximate that of tissues. Key roles in molecular pathways are played by adhesion complexes and the actinmyosin cytoskeleton, whose contractile forces are transmitted through transcellular structures. The feedback of local matrix stiffness on cell state likely has important implications for development, differentiation, disease, and regeneration.

...read moreread less

5,889 citations

"Matrix elasticity directs stem cell..." refers background in this paper

...Such a wide variation in matrix stiffness for differentiated cells is known to influence focal-adhesion structure and the cytoskeleton (Bershadsky et al., 2003; Cukierman et al., 2001; Discher et al., 2005; Engler et al., 2004a; Lo et al., 2000; Pelham and Wang, 1997)....
[...]

Journal Article•DOI•

CellProfiler: image analysis software for identifying and quantifying cell phenotypes

[...]

Anne E. Carpenter¹, Thouis R. Jones¹, Michael R. Lamprecht¹, Colin Clarke¹, In Han Kang¹, Ola Friman², David A. Guertin¹, Joo Han Chang¹, Robert A. Lindquist¹, Jason Moffat¹, Polina Golland¹, David M. Sabatini¹ - Show less +8 more•Institutions (2)

Massachusetts Institute of Technology¹, Brigham and Women's Hospital²

31 Oct 2006-Genome Biology

TL;DR: The first free, open-source system designed for flexible, high-throughput cell image analysis, CellProfiler is described, which can address a variety of biological questions quantitatively.

...read moreread less

Abstract: Biologists can now prepare and image thousands of samples per day using automation, enabling chemical screens and functional genomics (for example, using RNA interference). Here we describe the first free, open-source system designed for flexible, high-throughput cell image analysis, CellProfiler. CellProfiler can address a variety of biological questions quantitatively, including standard assays (for example, cell count, size, per-cell protein levels) and complex morphological assays (for example, cell/organelle shape or subcellular patterns of DNA or protein staining).

...read moreread less

4,578 citations

Journal Article•DOI•

Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment

[...]

Rowena McBeath¹, Dana M. Pirone¹, Celeste M. Nelson¹, Kiran Bhadriraju¹, Christopher S. Chen¹ - Show less +1 more•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Apr 2004-Developmental Cell

TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.

...read moreread less

3,995 citations

"Matrix elasticity directs stem cell..." refers background or result in this paper

...Similar results as above are found with a standard osteoblast induction media (OIM), which is known to promote cytoskeletal rearrangement and alkaline phosphatase production (Jaiswal et al., 1997; McBeath et al., 2004)....
[...]
...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell…...
[...]
...(McBeath et al., 2004; Wang et al., 2002)....
[...]
...Myosins in MSCs Couple Expression to Matrix Stiffness and Reveal a Key Role for NMM IIs Forces generated and/or imposed on the cell’s actin cytoskeleton have been postulated to influence differentiation (Engler et al., 2004a; Hinz et al., 2001; McBeath et al., 2004), but no past reports have hinted at strong, tissuedirected feedback of microenvironment elasticity on myosin expression or stem cell lineage specification....
[...]
...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell specification....
[...]

Journal Article•DOI•

Myofibroblasts and mechano-regulation of connective tissue remodelling

[...]

James J. Tomasek¹, Giulio Gabbiani², Boris Hinz², Christine Chaponnier², Robert A. Brown³ - Show less +1 more•Institutions (3)

University of Oklahoma Health Sciences Center¹, University of Geneva², Royal National Orthopaedic Hospital³

01 May 2002-Nature Reviews Molecular Cell Biology

TL;DR: It is clear that the understanding of the myofibroblast — its origins, functions and molecular regulation — will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.

...read moreread less

Abstract: During the past 20 years, it has become generally accepted that the modulation of fibroblastic cells towards the myofibroblastic phenotype, with acquisition of specialized contractile features, is essential for connective-tissue remodelling during normal and pathological wound healing. Yet the myofibroblast still remains one of the most enigmatic of cells, not least owing to its transient appearance in association with connective-tissue injury and to the difficulties in establishing its role in the production of tissue contracture. It is clear that our understanding of the myofibroblast its origins, functions and molecular regulation will have a profound influence on the future effectiveness not only of tissue engineering but also of regenerative medicine generally.

...read moreread less

3,836 citations

"Matrix elasticity directs stem cell..." refers background in this paper

...…Sweeney,1 and Dennis E. Discher1,2,3,4,* 1Pennsylvania Muscle Institute 2School of Engineering and Applied Science 3Cell & Molecular Biology Graduate Group 4Physics Graduate Group University of Pennsylvania, Philadelphia, PA 19104, USA *Contact: discher@seas.upenn.edu DOI 10.1016/j.cell.2006.06.044...
[...]
...…gels and wrinkling-silicone sheets also suggest some responsiveness to the physical state of the matrix (Hinz et al., 2001; Nakagawa et al., 1989; Tomasek et al., 2002; Wozniak et al., 2003), but gel porosity and film topography complicate identification of possible contributions of substrate…...
[...]