Cell therapies have the potential of being an effective approach for treating neurodegenerative conditions. However, the need for local delivery and the poor distribution of the transplanted cells hinder the development of effective treatments. Here, Shibuya et al. developed an efficient microglia replacement approach in rodents using circulation-derived myeloid cells (CDMCs). The cells broadly incorporated in the brain and generated microglia-like cells more efficiently than bone marrow transplant. In a mouse model of progressive neurodegeneration, CDMC-mediated microglia replacement reduced cell loss and brain inflammation, improved motor behavior, and extended life span. The results suggest that this approach might be therapeutic in multiple neurological conditions.
Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
This PDF file includes:
Other Supplementary Material for this manuscript includes the following:
Data file S1
Movies S1 and S2
REFERENCES AND NOTES
R. A. Barker, M. Parmar, L. Studer, J. Takahashi, Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: Dawn of a new era. Cell Stem Cell 21, 569–573 (2017).
Y. Tao, S. C. Vermilyea, M. Zammit, J. Lu, M. Olsen, J. M. Metzger, L. Yao, Y. Chen, S. Phillips, J. E. Holden, V. Bondarenko, W. F. Block, T. E. Barnhart, N. Schultz-Darken, K. Brunner, H. Simmons, B. T. Christian, M. E. Emborg, S.-C. Zhang, Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys. Nat. Med. 27, 632–639 (2021).
N. Gupta, R. G. Henry, J. Strober, S.-M. Kang, D. A. Lim, M. Bucci, E. Caverzasi, L. Gaetano, M. L. Mandelli, T. Ryan, R. Perry, J. Farrell, R. J. Jeremy, M. Ulman, S. L. Huhn, A. J. Barkovich, D. H. Rowitch, Neural stem cell engraftment and myelination in the human brain. Sci. Transl. Med. 4, 155ra137 (2012).
E. A. Copelan, Hematopoietic stem-cell transplantation. N. Engl. J. Med. 354, 1813–1826 (2006).
J. J. Malatack, D. M. Consolini, E. Bayever, The status of hematopoietic stem cell transplantation in lysosomal storage disease. Pediatr. Neurol. 29, 391–403 (2003).
J. J. Boelens, V. K. Prasad, J. Tolar, R. F. Wynn, C. Peters, Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr. Clin. North Am. 57, 123–145 (2010).
J. M. Rappeport, E. I. Ginns, Bone-marrow transplantation in severe Gaucher’s disease. N. Engl. J. Med. 311, 84–88 (1984).
O. Ringdén, C. G. Groth, A. Erikson, L. Bäckman, S. Granqvist, J. E. Månsson, L. Svennerholm, Long-term follow-up of the first successful bone marrow transplantation in Gaucher disease. Transplantation 46, 66–69 (1988).
B. Ajami, J. L. Bennett, C. Krieger, W. Tetzlaff, F. M. V. Rossi, Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
F. Ginhoux, M. Greter, M. Leboeuf, S. Nandi, P. See, S. Gokhan, M. F. Mehler, S. J. Conway, L. G. Ng, E. R. Stanley, I. M. Samokhvalov, M. Merad, Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
M. R. P. Elmore, A. R. Najafi, M. A. Koike, N. N. Dagher, E. E. Spangenberg, R. A. Rice, M. Kitazawa, B. Matusow, H. Nguyen, B. L. West, K. N. Green, Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).
E. Gomez Perdiguero, K. Klapproth, C. Schulz, K. Busch, E. Azzoni, L. Crozet, H. Garner, C. Trouillet, M. F. de Bruijn, F. Geissmann, H.-R. Rodewald, Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
P. Füger, J. K. Hefendehl, K. Veeraraghavalu, A.-C. Wendeln, C. Schlosser, U. Obermüller, B. M. Wegenast-Braun, J. J. Neher, P. Martus, S. Kohsaka, M. Thunemann, R. Feil, S. S. Sisodia, A. Skodras, M. Jucker, Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017).
M. F. Coutinho, J. I. Santos, S. Alves, Less is more: Substrate reduction therapy for lysosomal storage disorders. Int. J. Mol. Sci. 17, 1065 (2016).
Y. Sun, B. Liou, Z. Chu, V. Fannin, R. Blackwood, Y. Peng, G. A. Grabowski, H. W. Davis, X. Qi, Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease. EBioMedicine 55, 102735 (2020).
L. A. Hohsfield, A. R. Najafi, Y. Ghorbanian, N. Soni, E. E. Hingco, S. J. Kim, A. D. Jue, V. Swarup, M. A. Inlay, K. N. Green, Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS. J. Neuroinflammation 17, –279 (2020).
Z. Xu, Y. Rao, Y. Huang, T. Zhou, R. Feng, S. Xiong, T.-F. Yuan, S. Qin, Y. Lu, X. Zhou, X. Li, B. Qin, Y. Mao, B. Peng, Efficient strategies for microglia replacement in the central nervous system. Cell Rep. 32, 108041 (2020).
A. Capotondo, R. Milazzo, L. S. Politi, A. Quattrini, A. Palini, T. Plati, S. Merella, A. Nonis, C. di Serio, E. Montini, L. Naldini, A. Biffi, Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc. Natl. Acad. Sci. U.S.A. 109, 15018–15023 (2012).
A. Lampron, M. Lessard, S. Rivest, Effects of myeloablation, peripheral chimerism, and whole-body irradiation on the entry of bone marrow-derived cells into the brain. Cell Transplant. 21, 1149–1159 (2012).
A. Shemer, J. Grozovski, T. L. Tay, J. Tao, A. Volaski, P. Süß, A. Ardura-Fabregat, M. Gross-Vered, J.-S. Kim, E. David, L. Chappell-Maor, L. Thielecke, C. K. Glass, K. Cornils, M. Prinz, S. Jung, Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9, 5206 (2018).
F. L. Wilkinson, A. Sergijenko, K. J. Langford-Smith, M. Malinowska, R. F. Wynn, B. W. Bigger, Busulfan conditioning enhances engraftment of hematopoietic donor-derived cells in the brain compared with irradiation. Mol. Ther. 21, 868–876 (2013).
A. S. Youshani, S. Rowlston, C. O’Leary, G. Forte, H. Parker, A. Liao, B. Telfer, K. Williams, I. D. Kamaly-Asl, B. W. Bigger, Non-myeloablative busulfan chimeric mouse models are less pro-inflammatory than head-shielded irradiation for studying immune cell interactions in brain tumours. J. Neuroinflammation 16, 25 (2019).
J. Priller, A. Flügel, T. Wehner, M. Boentert, C. A. Haas, M. Prinz, F. Fernández-Klett, K. Prass, I. Bechmann, B. A. de Boer, M. Frotscher, G. W. Kreutzberg, D. A. Persons, U. Dirnagl, Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001).
F. C. Bennett, M. L. Bennett, F. Yaqoob, S. B. Mulinyawe, G. A. Grant, M. Hayden Gephart, E. D. Plowey, B. A. Barres, A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183.e8 (2018).
Y. Huang, Z. Xu, S. Xiong, F. Sun, G. Qin, G. Hu, J. Wang, L. Zhao, Y.-X. Liang, T. Wu, Z. Lu, M. S. Humayun, K.-F. So, Y. Pan, N. Li, T.-F. Yuan, Y. Rao, B. Peng, Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat. Neurosci. 21, 530–540 (2018).
N. N. Dagher, A. R. Najafi, K. M. N. Kayala, M. R. P. Elmore, T. E. White, R. Medeiros, B. L. West, K. N. Green, Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflammation 12, 139 (2015).
M. Valdearcos, J. D. Douglass, M. M. Robblee, M. D. Dorfman, D. R. Stifler, M. L. Bennett, I. Gerritse, R. Fasnacht, B. A. Barres, J. P. Thaler, S. K. Koliwad, Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 26, 185–197.e3 (2017).
J. C. Cronk, A. J. Filiano, A. Louveau, I. Marin, R. Marsh, E. Ji, D. H. Goldman, I. Smirnov, N. Geraci, S. Acton, C. C. Overall, J. Kipnis, Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med. 215, 1627–1647 (2018).
H. Lund, M. Pieber, R. Parsa, J. Han, D. Grommisch, E. Ewing, L. Kular, M. Needhamsen, A. Espinosa, E. Nilsson, A. K. Överby, O. Butovsky, M. Jagodic, X.-M. Zhang, R. A. Harris, Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun. 9, 4845 (2018).
Q. Li, B. A. Barres, Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018).
M. W. Salter, B. Stevens, Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).
H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland, E. David, K. Baruch, D. Lara-Astaiso, B. Toth, S. Itzkovitz, M. Colonna, M. Schwartz, I. Amit, A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017).
S. Krasemann, C. Madore, R. Cialic, C. Baufeld, N. Calcagno, R. El Fatimy, L. Beckers, E. O’Loughlin, Y. Xu, Z. Fanek, D. J. Greco, S. T. Smith, G. Tweet, Z. Humulock, T. Zrzavy, P. Conde-Sanroman, M. Gacias, Z. Weng, H. Chen, E. Tjon, F. Mazaheri, K. Hartmann, A. Madi, J. D. Ulrich, M. Glatzel, A. Worthmann, J. Heeren, B. Budnik, C. Lemere, T. Ikezu, F. L. Heppner, V. Litvak, D. M. Holtzman, H. Lassmann, H. L. Weiner, J. Ochando, C. Haass, O. Butovsky, The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581.e9 (2017).
C. E. G. Leyns, J. D. Ulrich, M. B. Finn, F. R. Stewart, L. J. Koscal, J. R. Serrano, G. O. Robinson, E. Anderson, M. Colonna, D. M. Holtzman, TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl. Acad. Sci. U.S.A. 114, 11524–11529 (2017).
M. Olah, E. Patrick, A.-C. Villani, J. Xu, C. C. White, K. J. Ryan, P. Piehowski, A. Kapasi, P. Nejad, M. Cimpean, S. Connor, C. J. Yung, M. Frangieh, A. McHenry, W. Elyaman, V. Petyuk, J. A. Schneider, D. A. Bennett, P. L. De Jager, E. M. Bradshaw, A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018).
M. L. Bennett, F. C. Bennett, S. A. Liddelow, B. Ajami, J. L. Zamanian, N. B. Fernhoff, S. B. Mulinyawe, C. J. Bohlen, A. Adil, A. Tucker, I. L. Weissman, E. F. Chang, G. Li, G. A. Grant, M. G. Hayden Gephart, B. A. Barres, New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. U.S.A. 113, E1738–E1746 (2016).
K. I. Mosher, T. Wyss-Coray, Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594–604 (2014).
D. Davalos, J. Grutzendler, G. Yang, J. V. Kim, Y. Zuo, S. Jung, D. R. Littman, M. L. Dustin, W.-B. Gan, ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).
A. Nimmerjahn, F. Kirchhoff, F. Helmchen, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
T. Goldmann, P. Wieghofer, P. F. Müller, Y. Wolf, D. Varol, S. Yona, S. M. Brendecke, K. Kierdorf, O. Staszewski, M. Datta, T. Luedde, M. Heikenwalder, S. Jung, M. Prinz, A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 1618–1626 (2013).
J. Seita, I. L. Weissman, Hematopoietic stem cell: Self-renewal versus differentiation. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 640–653 (2010).
S. Hamanaka, J. Ooehara, Y. Morita, H. Ema, S. Takahashi, A. Miyawaki, M. Otsu, T. Yamaguchi, M. Onodera, H. Nakauchi, Generation of transgenic mouse line expressing Kusabira Orange throughout body, including erythrocytes, by random segregation of provirus method. Biochem. Biophys. Res. Commun. 435, 586–591 (2013).
Y. Sun, B. Quinn, D. P. Witte, G. A. Grabowski, Gaucher disease mouse models: Point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants. J. Lipid Res. 46, 2102–2113 (2005).
V. Schiffer, E. Santiago-Mujika, S. Flunkert, S. Schmidt, M. Farcher, T. Loeffler, I. Schilcher, M. Posch, J. Neddens, Y. Sun, J. Kehr, B. Hutter-Paier, Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease. PLOS ONE 15, e0227077 (2020).
Y.-H. Xu, B. Quinn, D. Witte, G. A. Grabowski, Viable mouse models of acid beta-glucosidase deficiency: The defect in Gaucher disease. Am. J. Pathol. 163, 2093–2101 (2003).
Y. Sun, L. Jia, M. T. Williams, M. Zamzow, H. Ran, B. Quinn, B. J. Aronow, C. V. Vorhees, D. P. Witte, G. A. Grabowski, Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice. BMC Neurosci. 9, 76 (2008).
Y. Sun, W. Zhang, Y.-H. Xu, B. Quinn, N. Dasgupta, B. Liou, K. D. R. Setchell, G. A. Grabowski, Substrate compositional variation with tissue/region and Gba1 mutations in mouse models–implications for Gaucher disease. PLOS ONE 8, e57560 (2013).
L. Calderwood, D. A. Wenger, D. Matern, H. Dahmoush, V. Watiker, C. Lee, Rare Saposin A deficiency: Novel variant and psychosine analysis. Mol. Genet. Metab. 129, 161–164 (2020).
R. Spiegel, G. Bach, V. Sury, G. Mengistu, B. Meidan, S. Shalev, Y. Shneor, H. Mandel, M. Zeigler, A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: First report of saposin A deficiency in humans. Mol. Genet. Metab. 84, 160–166 (2005).
A. Diaz-Font, B. Cormand, R. Santamaria, L. Vilageliu, D. Grinberg, A. Chabás, A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity. Hum. Genet. 117, 275–277 (2005).
M. Cesani, L. Lorioli, S. Grossi, G. Amico, F. Fumagalli, I. Spiga, M. Filocamo, A. Biffi, Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum. Mutat. 37, 16–27 (2016).
M. Hiraiwa, B. M. Martin, Y. Kishimoto, G. E. Conner, S. Tsuji, J. S. O’Brien, Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins)—Its mechanism and inhibition by ganglioside. Arch. Biochem. Biophys. 341, 17–24 (1997).
T. Leonova, X. Qi, A. Bencosme, E. Ponce, Y. Sun, G. A. Grabowski, Proteolytic processing patterns of prosaposin in insect and mammalian cells. J. Biol. Chem. 271, 17312–17320 (1996).
T. Hiesberger, S. Hüttler, A. Rohlmann, W. Schneider, K. Sandhoff, J. Herz, Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor-related protein (LRP). EMBO J. 17, 4617–4625 (1998).
Z. I. Remec, K. Trebusak Podkrajsek, B. Repic Lampret, J. Kovac, U. Groselj, T. Tesovnik, T. Battelino, M. Debeljak, Next-generation sequencing in newborn screening: A review of current state. Front. Genet. 12, 662254 (2021).
A. C. Wilkinson, R. Ishida, M. Kikuchi, K. Sudo, M. Morita, R. V. Crisostomo, R. Yamamoto, K. M. Loh, Y. Nakamura, M. Watanabe, H. Nakauchi, S. Yamazaki, Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature 571, 117–121 (2019).
J. Hanna, M. Wernig, S. Markoulaki, C.-W. Sun, A. Meissner, J. P. Cassady, C. Beard, T. Brambrink, L.-C. Wu, T. M. Townes, R. Jaenisch, Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2007).
E. B. Vitner, T. Farfel-Becker, R. Eilam, I. Biton, A. H. Futerman, Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain 135, 1724–1735 (2012).
A. Chhabra, A. M. Ring, K. Weiskopf, P. J. Schnorr, S. Gordon, A. C. Le, H.-S. Kwon, N. G. Ring, J. Volkmer, P. Y. Ho, S. Tseng, I. L. Weissman, J. A. Shizuru, Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci. Transl. Med. 8, 351ra105 (2016).
B. M. George, K. S. Kao, H.-S. Kwon, B. J. Velasco, J. Poyser, A. Chen, A. C. Le, A. Chhabra, C. E. Burnett, D. Cajuste, M. Hoover, K. M. Loh, J. A. Shizuru, I. L. Weissman, Antibody conditioning enables MHC-mismatched hematopoietic stem cell transplants and organ graft tolerance. Cell Stem Cell 25, 185–192.e3 (2019).
T. Matsuda, T. Irie, S. Katsurabayashi, Y. Hayashi, T. Nagai, N. Hamazaki, A. M. D. Adefuin, F. Miura, T. Ito, H. Kimura, K. Shirahige, T. Takeda, K. Iwasaki, T. Imamura, K. Nakashima, Pioneer factor NeuroD1 rearranges transcriptional and epigenetic profiles to execute microglia-neuron conversion. Neuron 101, 472–485.e7 (2019).
Y. Shibuya, C. C. Y. Chang, L.-H. Huang, E. Y. Bryleva, T.-Y. Chang, Inhibiting ACAT1/SOAT1 in microglia stimulates autophagy-mediated lysosomal proteolysis and increases Aβ1–42 clearance. J. Neurosci. 34, 14484–14501 (2014).
K. Young, H. Morrison, Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. J. Vis. Exp. , e57648 (2018).
C. J. Henry, Y. Huang, A. Wynne, M. Hanke, J. Himler, M. T. Bailey, J. F. Sheridan, J. P. Godbout, Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation 5, 15 (2008).
M. A. Mohr, D. Bushey, A. Aggarwal, J. S. Marvin, J. J. Kim, E. J. Marquez, Y. Liang, R. Patel, J. J. Macklin, C.-Y. Lee, A. Tsang, G. Tsegaye, A. M. Ahrens, J. L. Chen, D. S. Kim, A. M. Wong, L. L. Looger, E. R. Schreiter, K. Podgorski, jYCaMP: An optimized calcium indicator for two-photon imaging at fiber laser wavelengths. Nat. Methods 17, 694–697 (2020).
M. W. Pfaffl, G. W. Horgan, L. Dempfle, Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30, e36 (2002).
R. Yamamoto, A. C. Wilkinson, J. Ooehara, X. Lan, C.-Y. Lai, Y. Nakauchi, J. K. Pritchard, H. Nakauchi, Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell 22, 600–607.e4 (2018).
M. Faizi, P. L. Bader, N. Saw, T.-V. V. Nguyen, S. Beraki, T. Wyss-Coray, F. M. Longo, M. Shamloo, Thy1-hAPPLond/Swe+ mouse model of Alzheimer’s disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain Behav. 2, 142–154 (2012).
S. C. Fowler, B. R. Birkestrand, R. Chen, S. J. Moss, E. Vorontsova, G. Wang, T. J. Zarcone, A force-plate actometer for quantitating rodent behaviors: Illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor. J. Neurosci. Methods 107, 107–124 (2001).
Science Translational Medicine
Volume 14 | Issue 636
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Received: 19 August 2021
Accepted: 10 February 2022
Request permissions for this article.
We would like to thank all members of the Wernig laboratory, J. Pluvinage, D. Mochly-Rosen, and K. Grimes for helpful discussions throughout the project and T. Broer, M. R. Casilla, FACS core at Institute for Stem Cell Biology and Regenerative Medicine, and Stanford Neuroscience Microscopy Service (supported by NIH NS069375) for technical support.
Funding: The project was supported by a pilot grant from the Stanford Alzheimer’s Disease Research Center NIH grant (P50AG047366 to M.W.), Howard Hughes Medical Institute Faculty Scholar Award, and the Goldman-Sachs Foundation to M.W. Y. Shibuya was supported by the Larry L. Hillblom Foundation Postdoctoral Fellowship (2017-A-016-FEL). K.K.K. was supported by the Stanford Neurosurgery Resident Research Education Program R25 (NIH NS065741-10). M.M.-D.M. was supported by Deutsche Forschungsgemeinschaft (DFG) (MA 8492/1-1). Y.Y. was supported by the New York Stem Cell Foundation Druckenmiller Fellowship (NYSCF–D–F74). L.A.A. was supported by grants from the NIH and California Institute of Regenerative Medicine (CIRM) awarded to L.A.A.’s home institution, San Francisco State University (R25-GM059298, CIRM:EDUC2-08391).
Author contributions: Study concept and design: Y. Shibuya and M.W. BMT and posttransplantation analyses: Y. Shibuya, K.K.K., M.M.-D.M., Y.Y., L.A.A., I.K., R.Y., and P.M. RNA-seq data processing: Y.Y. Two-photon microscopy: M.M.-D.M. and M.A.M. Droplet digital PCR: G.N. Behavioral tests: K.K.K. and M.Z. Development and maintenance of Psap-deficient mice: B.L. and Y. Sun. Supervision and suggestions on data interpretation: T.C.S., T.W.-C., F.L.H., X.C., Y. Sun, H.N., and F.C.B. Drafting of original manuscript: Y. Shibuya and M.W. All authors reviewed, revised, and approved the final version of the paper.
Competing interests: The authors declare that they have no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. The bulk RNA-seq dataset generated in this study is available at the NCBI BioProject (www.ncbi.nlm.nih.gov/bioproject), accession no: PRJNA600501. PLX5622 was provided by Plexxikon Inc. under a material transfer agreement between Stanford University and Plexxikon Inc.
National Institutes of Health: NS065741-10
National Institutes of Health: R25-GM059298
National Institute on Aging: P50AG047366
California Institute for Regenerative Medicine: CIRM:EDUC2-08391
Larry L. Hillblom Foundation: 2017-A-016-FEL
New York Stem Cell Foundation: NYSCF?D?F74
Deutsche Forschungsgemeinschaft: MA 8492/1-1
Select the format you want to export the citation of this publication.
Download this article as a PDF fileDownload PDF