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Deteriorating Infrastructure in the Aged Muscle Stem Cell Niche
Cell Stem Cell
Previews Zriwil, A., Lutteropp, M., Grover, A., et al. (2016). Nat. Immunol. 17, 666–676.
N., Yosef, N., Chang, C.Y., Shay, T., et al. (2011). Cell 144, 296–309.
Haas, S., Hansson, J., Klimmeck, D., Loeffler, D., Velten, L., Uckelmann, H., Wurzer, S., Prendergast, A.M., Schnell, A., Hexel, K., et al. (2015). Cell Stem Cell 17, 422–434.
Orkin, S.H., and Zon, L.I. (2008). Cell 132, 631–644.
Sanjuan-Pla, A., Macaulay, I.C., Jensen, C.T., Woll, P.S., Luis, T.C., Mead, A., Moore, S., Carella, C., Matsuoka, S., Bouriez Jones, T., et al. (2013). Nature 502, 232–236.
Paul, F., Arkin, Y., Giladi, A., Jaitin, D.A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., et al. (2015). Cell 163, 1663–1677.
Yamamoto, R., Morita, Y., Ooehara, J., Hamanaka, S., Onodera, M., Rudolph, K.L., Ema, H., and Nakauchi, H. (2013). Cell 154, 1112– 1126.
Novershtern, N., Subramanian, A., Lawton, L.N., Mak, R.H., Haining, W.N., McConkey, M.E., Habib,
Deteriorating Infrastructure in the Aged Muscle Stem Cell Niche Joseph T. Rodgers1,* 1Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2016.07.008
Following an injury, the extracellular matrix (ECM) undergoes dramatic remodeling to facilitate tissue repair. In a new study, Lukjanenko and colleagues show how an age-associated change in this process affects the regenerative ability of muscle stem cells (MuSCs). Introduction One of the hallmarks of aging is a decline in the ability to heal from injury. Impaired healing represents an enormous medical problem and quality of life issue for the elderly (Gosain and DiPietro, 2004). Consequently, understanding how tissue repair changes with age is a topic with important implications. Much work has focused on direct comparisons between ‘‘young’’ and ‘‘aged’’ somatic stem cells, which play crucial roles in tissue repair, without elucidating the origin of the age-associated differences between them (Liu and Rando, 2011). In a recent report, Lukjanenko and colleagues (Lukjanenko et al., 2016) provide an explanation of why aged muscle stem cells (MuSCs) become defective at repairing muscle: the response of MuSCs to an age-associated change in the extracellular matrix (ECM) of the stem cell niche. The importance of the ECM as it relates to stem cell function in normal tissue biology and repair cannot be overstated. The ECM is the infrastructure and structure of a tissue, the substrate upon which stem cells reside, and a conveyer and scaffold of signaling molecules (Frantz et al., 2010). Following injury, the ECM is
dynamically remodeled to support the process of tissue repair. Fibronectin (FN), one of the core components of the ECM, is deposited in large quantities in damaged tissues following injury. Consistent with previous findings (Ashcroft et al., 1997; Bentzinger et al., 2013), Lukjanenko and colleagues report that aged mice had reduced FN deposition in injured muscle tissue. Among its many functions, FN serves as an adhesion substrate for stem and progenitor cells. Interestingly, in a competitive screen of ECM components, myoblasts bound more avidly to FN then to any other component of the ECM. Combined, these findings suggested that the reduction of FN, the preferred adhesion substrate of myoblasts, in injured aged muscle might affect the ability of MuSCs to repair muscle damage. In testing this idea, Lukjanenko and colleagues used a combination of model systems, myoblast cell lines, primary MuSCs, and in vivo muscle repair and found that many defective aspects of MuSC function and muscle repair in aged mice could be restored by increasing FN levels. Lukjanenko and colleagues go on to show that the mechanism by which
150 Cell Stem Cell 19, August 4, 2016 ª 2016 Elsevier Inc.
FN improves aged MuSC function is through FN’s role as a biochemical signaling molecule. Interestingly, myoblasts cultured on FN displayed a reduction in signaling through the p38 and ERK pathways when compared to myoblasts cultured on laminin (a component of the ECM and a commonly used cell culture substrate). The p38 and ERK signaling pathways are known to be elevated in aged MuSCs with detrimental effects (Bernet et al., 2014; Chakkalakal et al., 2012). Culturing aged MuSCs on FN was sufficient to restore their cell adhesion properties and to reduce apoptosis—two aspects of aged MuSC function that were defective when they were cultured on collagen (another component of the ECM and a commonly used cell culture substrate). Together, these experiments suggest that FN provides signals that instruct the appropriate functional behaviors of MuSCs. Furthermore, the experiments suggest that dysfunction of aged MuSCs is the consequence of lower levels of FN in injured aged mice. Indeed, in testing this hypothesis, it was found that injection of purified exogenous FN into previously injured muscles restored several aspects of
Cell Stem Cell
Previews MuSC function and muscle regeneration in aged mice. This interesting set of findings supports a model in which changes in the aged stem cell niche impart a dysfunctional state in the aged stem cells that reduces their regenerative abilities. Importantly, normal or ‘‘young’’ niche signals can restore at least some aspects of stem cell function and tissue repair in aged mice. It is well known that the structure, composition, crosslinking, and stiffness of the ECM changes in many tissues of the body through the course of aging (Labat-Robert and Robert, 1988). Using a collection of aptamers to measure the abundance of various ECM proteins, the authors detected several age-associated changes in uninjured muscle tissue. However, these modest changes in uninjured tissue were dwarfed by the reorganization of the ECM, and particularly of FN, that occurred following injury. Importantly, aged animals did not appear to have the same injury-induced reorganization of the ECM that young animals did. Because of the many important roles of the ECM, it
is easy to envision how these differences could affect the function of stem cells and dramatically impact the ability to heal injuries. So, what is responsible for the ageassociated changes to the ECM? At least in terms of injury-induced FN deposition, the authors provide some critical clues. They made a very interesting observation that Lin+ cells (CD31+, CD44+, CD11b+), a mixture of circulating hematopoietic and immune cells and endothelial cells, were the largest contributors of FN in injured muscle. In aged mice, there was a dramatic decline in the number of these cells found in injured muscle. These findings are intriguing because FN deposition has important roles in the healing of many different types of tissues. Though it is difficult to assign FN deposition to a particular cell type, many are known to express FN, and soluble FN is an extremely abundant component of blood. If a population of circulating cells were responsible for the decline in FN deposition at sites of injury, this may be a mechanism that underlies the decline in
healing that occurs throughout the body with age. REFERENCES Ashcroft, G.S., Horan, M.A., and Ferguson, M.W. (1997). J. Invest. Dermatol. 108, 430–437. Bentzinger, C.F., Wang, Y.X., von Maltzahn, J., Soleimani, V.D., Yin, H., and Rudnicki, M.A. (2013). Cell Stem Cell 12, 75–87. Bernet, J.D., Doles, J.D., Hall, J.K., Kelly Tanaka, K., Carter, T.A., and Olwin, B.B. (2014). Nat. Med. 20, 265–271. Chakkalakal, J.V., Jones, K.M., Basson, M.A., and Brack, A.S. (2012). Nature 490, 355–360. Frantz, C., Stewart, K.M., and Weaver, V.M. (2010). J. Cell Sci. 123, 4195–4200. Gosain, A., and DiPietro, L.A. (2004). World J. Surg. 28, 321–326. Labat-Robert, J., and Robert, L. (1988). Exp. Gerontol. 23, 5–18. Liu, L., and Rando, T.A. (2011). J. Cell Biol. 193, 257–266. Lukjanenko, L., Jung, M.J., Hegde, N., Perruisseau-Carrier, C., Migliavacca, E., Rozo, M., Karaz, S., Jacot, G., Schmidt, M., Li, L., et al. (2016). Nat. Med., Published online July 4, 2016. http://dx.doi. org/10.1038/nm.4126.
Cell Stem Cell 19, August 4, 2016 151
Previews Zriwil, A., Lutteropp, M., Grover, A., et al. (2016). Nat. Immunol. 17, 666–676.
N., Yosef, N., Chang, C.Y., Shay, T., et al. (2011). Cell 144, 296–309.
Haas, S., Hansson, J., Klimmeck, D., Loeffler, D., Velten, L., Uckelmann, H., Wurzer, S., Prendergast, A.M., Schnell, A., Hexel, K., et al. (2015). Cell Stem Cell 17, 422–434.
Orkin, S.H., and Zon, L.I. (2008). Cell 132, 631–644.
Sanjuan-Pla, A., Macaulay, I.C., Jensen, C.T., Woll, P.S., Luis, T.C., Mead, A., Moore, S., Carella, C., Matsuoka, S., Bouriez Jones, T., et al. (2013). Nature 502, 232–236.
Paul, F., Arkin, Y., Giladi, A., Jaitin, D.A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., et al. (2015). Cell 163, 1663–1677.
Yamamoto, R., Morita, Y., Ooehara, J., Hamanaka, S., Onodera, M., Rudolph, K.L., Ema, H., and Nakauchi, H. (2013). Cell 154, 1112– 1126.
Novershtern, N., Subramanian, A., Lawton, L.N., Mak, R.H., Haining, W.N., McConkey, M.E., Habib,
Deteriorating Infrastructure in the Aged Muscle Stem Cell Niche Joseph T. Rodgers1,* 1Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2016.07.008
Following an injury, the extracellular matrix (ECM) undergoes dramatic remodeling to facilitate tissue repair. In a new study, Lukjanenko and colleagues show how an age-associated change in this process affects the regenerative ability of muscle stem cells (MuSCs). Introduction One of the hallmarks of aging is a decline in the ability to heal from injury. Impaired healing represents an enormous medical problem and quality of life issue for the elderly (Gosain and DiPietro, 2004). Consequently, understanding how tissue repair changes with age is a topic with important implications. Much work has focused on direct comparisons between ‘‘young’’ and ‘‘aged’’ somatic stem cells, which play crucial roles in tissue repair, without elucidating the origin of the age-associated differences between them (Liu and Rando, 2011). In a recent report, Lukjanenko and colleagues (Lukjanenko et al., 2016) provide an explanation of why aged muscle stem cells (MuSCs) become defective at repairing muscle: the response of MuSCs to an age-associated change in the extracellular matrix (ECM) of the stem cell niche. The importance of the ECM as it relates to stem cell function in normal tissue biology and repair cannot be overstated. The ECM is the infrastructure and structure of a tissue, the substrate upon which stem cells reside, and a conveyer and scaffold of signaling molecules (Frantz et al., 2010). Following injury, the ECM is
dynamically remodeled to support the process of tissue repair. Fibronectin (FN), one of the core components of the ECM, is deposited in large quantities in damaged tissues following injury. Consistent with previous findings (Ashcroft et al., 1997; Bentzinger et al., 2013), Lukjanenko and colleagues report that aged mice had reduced FN deposition in injured muscle tissue. Among its many functions, FN serves as an adhesion substrate for stem and progenitor cells. Interestingly, in a competitive screen of ECM components, myoblasts bound more avidly to FN then to any other component of the ECM. Combined, these findings suggested that the reduction of FN, the preferred adhesion substrate of myoblasts, in injured aged muscle might affect the ability of MuSCs to repair muscle damage. In testing this idea, Lukjanenko and colleagues used a combination of model systems, myoblast cell lines, primary MuSCs, and in vivo muscle repair and found that many defective aspects of MuSC function and muscle repair in aged mice could be restored by increasing FN levels. Lukjanenko and colleagues go on to show that the mechanism by which
150 Cell Stem Cell 19, August 4, 2016 ª 2016 Elsevier Inc.
FN improves aged MuSC function is through FN’s role as a biochemical signaling molecule. Interestingly, myoblasts cultured on FN displayed a reduction in signaling through the p38 and ERK pathways when compared to myoblasts cultured on laminin (a component of the ECM and a commonly used cell culture substrate). The p38 and ERK signaling pathways are known to be elevated in aged MuSCs with detrimental effects (Bernet et al., 2014; Chakkalakal et al., 2012). Culturing aged MuSCs on FN was sufficient to restore their cell adhesion properties and to reduce apoptosis—two aspects of aged MuSC function that were defective when they were cultured on collagen (another component of the ECM and a commonly used cell culture substrate). Together, these experiments suggest that FN provides signals that instruct the appropriate functional behaviors of MuSCs. Furthermore, the experiments suggest that dysfunction of aged MuSCs is the consequence of lower levels of FN in injured aged mice. Indeed, in testing this hypothesis, it was found that injection of purified exogenous FN into previously injured muscles restored several aspects of
Cell Stem Cell
Previews MuSC function and muscle regeneration in aged mice. This interesting set of findings supports a model in which changes in the aged stem cell niche impart a dysfunctional state in the aged stem cells that reduces their regenerative abilities. Importantly, normal or ‘‘young’’ niche signals can restore at least some aspects of stem cell function and tissue repair in aged mice. It is well known that the structure, composition, crosslinking, and stiffness of the ECM changes in many tissues of the body through the course of aging (Labat-Robert and Robert, 1988). Using a collection of aptamers to measure the abundance of various ECM proteins, the authors detected several age-associated changes in uninjured muscle tissue. However, these modest changes in uninjured tissue were dwarfed by the reorganization of the ECM, and particularly of FN, that occurred following injury. Importantly, aged animals did not appear to have the same injury-induced reorganization of the ECM that young animals did. Because of the many important roles of the ECM, it
is easy to envision how these differences could affect the function of stem cells and dramatically impact the ability to heal injuries. So, what is responsible for the ageassociated changes to the ECM? At least in terms of injury-induced FN deposition, the authors provide some critical clues. They made a very interesting observation that Lin+ cells (CD31+, CD44+, CD11b+), a mixture of circulating hematopoietic and immune cells and endothelial cells, were the largest contributors of FN in injured muscle. In aged mice, there was a dramatic decline in the number of these cells found in injured muscle. These findings are intriguing because FN deposition has important roles in the healing of many different types of tissues. Though it is difficult to assign FN deposition to a particular cell type, many are known to express FN, and soluble FN is an extremely abundant component of blood. If a population of circulating cells were responsible for the decline in FN deposition at sites of injury, this may be a mechanism that underlies the decline in
healing that occurs throughout the body with age. REFERENCES Ashcroft, G.S., Horan, M.A., and Ferguson, M.W. (1997). J. Invest. Dermatol. 108, 430–437. Bentzinger, C.F., Wang, Y.X., von Maltzahn, J., Soleimani, V.D., Yin, H., and Rudnicki, M.A. (2013). Cell Stem Cell 12, 75–87. Bernet, J.D., Doles, J.D., Hall, J.K., Kelly Tanaka, K., Carter, T.A., and Olwin, B.B. (2014). Nat. Med. 20, 265–271. Chakkalakal, J.V., Jones, K.M., Basson, M.A., and Brack, A.S. (2012). Nature 490, 355–360. Frantz, C., Stewart, K.M., and Weaver, V.M. (2010). J. Cell Sci. 123, 4195–4200. Gosain, A., and DiPietro, L.A. (2004). World J. Surg. 28, 321–326. Labat-Robert, J., and Robert, L. (1988). Exp. Gerontol. 23, 5–18. Liu, L., and Rando, T.A. (2011). J. Cell Biol. 193, 257–266. Lukjanenko, L., Jung, M.J., Hegde, N., Perruisseau-Carrier, C., Migliavacca, E., Rozo, M., Karaz, S., Jacot, G., Schmidt, M., Li, L., et al. (2016). Nat. Med., Published online July 4, 2016. http://dx.doi. org/10.1038/nm.4126.
Cell Stem Cell 19, August 4, 2016 151