Regenerative Medicine

Naoki Nakayama, PhD
Principal Investigator & Program Director of Stem Cell Engineering and Cartilage Regeneration

Naoki Nakayama, PhD, joined Steadman Philippon Research Institute (SPRI) in November 2020, initiating a new project focusing on cartilage regeneration and stem cell engineering, after spending eleven years as Associate Professor in the Institute of Molecular Medicine (IMM), the University of Texas Health Science Center at Houston (UTHealth) McGovern Medical School. He also belonged to the Department of Orthopaedic Surgery, UTHealth McGovern Medical School, when Johnny Huard, PhD, Director of the Linda & Mitch Hart Center for Regenerative and Personalized Medicine (CRPM) and Chief Scientific Officer (CSO) of SPRI, served as Vice Chair for Research.

Naoki graduated from the University of Tokyo (Faculty of Science), Tokyo, Japan, with a major in biophysics and biochemistry. He then joined the Department of Chemistry in the Institute of Medical Science, the University of Tokyo (IMSUT), led by Dr. Yoshito Kaziro (a foreign member of NAS from the United States) as a graduate student. However, as his mentor Dr. Ken-ichi Arai who returned to IMSUT from Stanford University quickly moved back to California (DNAX Research Institute, founded by Drs. Arthur Kornberg, Paul Berg, and Charles Yanofsky at Stanford University), Naoki had an opportunity to complete his PhD thesis on “Molecular genetics of the G-protein coupled receptor signal transduction in yeast” through help from Dr. Arthur Kornberg at Stanford, and continue work as a postdoc under Dr. Arai in DNAX. Naoki was impressed with the scientifically open and stimulating atmosphere that DNAX provided, and the power of such a pseudo-academic biotech company to advance science. This experience inspired him to do science outside of Japan, even in an industrial setting. Although he was appointed as Assistant Professor (called Joshu) in IMSUT in Tokyo, he decided to move back to California as Principal Investigator (PI) at Amgen, Inc., and participated in various basic/discovery research in the area of developmental hematopoiesis, using mouse embryonic stem cells (ESCs), as well as in drug discovery research in the area of bone and cartilage diseases. He later took a PI position in Australia for human ESC works as a step toward returning to the academic world.
 
Naoki is a pluripotent stem cell (PSC) specialist. As PI at Peter MacCallum Cancer Institute and Australian Stem Cell Centre (ASCC) in Melbourne, Australia, and then as Associate Professor in IMM UTHealth in Houston, his research has been focusing on basic as well as translational aspects of human embryonic hemogenesis and skeletogenesis using human PSCs—such as ESCs and induced pluripotent stem cells (iPSCs)—as a model system; he established an unbroken track record. PSCs tend to generate embryonic/fetal cell types. During our fetal life, many important functional cells are newly generated. For example, our joint cartilage is newly developed during limb development. Naoki believes that rejuvenation is one of the keys for success in regenerative medicine for some adult tissues such as intrajoint cartilage and ligament. Therefore, he considers that basic and translational studies of human iPSC-derived tissue-specific fetal progenitor cells (e.g., joint progenitor cells) are important, since the iPSC technology is thus far the only reliable cellular rejuvenation technology to obtain fetal cells from elderly patients.

Supported by the NIH and other external funding sources, Naoki will not only expand the research on the human PSC-derived joint cartilage-forming cells, but also conduct new cartilage research programs, which will complement SPRI’s clinical expertise and current research portfolio. He is also interested in mentoring young researchers and visiting fellows at SPRI.

Contributions to cartilage research

1. Mouse ESCs to mesodermal chondrocytes. Briefly in Amgen and later in IMM UTHealth Medical School, Naoki’s group worked on cartilage biology for identifying genes/targets for cartilage regeneration. As part of the effort, he discovered two novel BMP-binding inhibitors, Chordin-like 1 (CHRDL1) and Chordin-like 2 (CHRDL2) that are expressed in the hypertrophic zone of growth plate (Nakayama, et al., 2001) and in the superficial zone of developing joint articular cartilage (Nakayama, et al., 2004), respectively. His group has also made significant progress in understanding the cellular basis of mouse ESC-differentiation toward mesodermal chondroprogenitor cells (Nakayama, et al., 2003; Tanaka, et al., 2009; Zhao, et al., 2014), which was used for establishing a novel cell-based chondrogenesis assay tool for compound screening. His team also developed and ran cell-based, high-throughput assays for small molecule as well as antibody drug development of G-protein coupled receptors (GPCRs), and secreted proteins.
   1. Nakayama N, Han CE, Scully S, Nishinakamura R, He C, Zeni L, et al. A novel chordin-like protein inhibitor for bone morphogenetic proteins expressed preferentially in mesenchymal cell lineages. Dev Biol. 2001;232.(2):372-87. PMI: 11401399
   2. Nakayama N, Duryea D, Manoukian R, Chow G, Han CY. Macroscopic cartilage formation with embryonic stem-cell-derived mesodermal progenitor cells. J Cell Sci. 2003;116(Pt 10):2015-28. PMI: 12679385
   3. Nakayama N, Han CY, Cam L, Lee JI, Pretorius J, Fisher S, et al. A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage. Development. 2004;131(1):229-40. PMI: 14660436
   4. Tanaka M, Jokubaitis V, Wood C, Wang Y, Brouard N, Pera M, et al. BMP inhibition stimulates WNT-dependent generation of chondrogenic mesoderm from embryonic stem cells. Stem Cell Res. 2009;3(2-3):126-141. PMI: 19700382 Nakayama N, corresponding author
   5. Zhao J, Li S, Trilok S, Tanaka M, Jokubaitis-Jameson V, Wang B, et al. Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells. Development. 2014;141(20):3848-58. PMI: 25294938 Nakayama N, corresponding author
       
2. Developing germ layer-specific (i.e., mesoderm and neural crest-derived) chondrocytes from human PSCs. At ASCC, Naoki headed a research group focusing on the human PSC biology for establishing directed differentiation culture methods towards specific multipotential stem cell types. His group made significant progress in understanding the signaling principle (like WNT-BMP-Nodal feed forward mechanism) and cellular developmental pathways for the genesis of lateral plate mesoderm from human PSCs (i.e., ESCs and iPSCs). Naoki’s latest publications from IMM have been focusing on establishing directed differentiation culture methods for human PSCs towards specific embryonic chondroprogenitor cell types including sclerotome of paraxial mesoderm and ectomesenchyme of neural crest. His lab has made significant progress in understanding the signaling principle and cellular pathways for the genesis of SOX9+ chondrogenic (i.e., sclerotome-like) paraxial mesoderm (Umeda, et al., 2012) and ectomesenchyme (Umeda et al, 2015) from human ESCs and iPSCs, leading to OSR1+ intermediate mesoderm formation (Mae, et al., 2013), too. This program is aiming to solve two major problems that adult MSCs face regarding their application to cartilage repair: 1) preparation of many chondrogenically active cells, and 2) controlling maturation of the regenerated chondrocytes. Naoki’s group has made a breakthrough to the 1st problem using neural crest-derived ectomesenchymal cells: i.e., long-term expansion without loss of chondrogenic activity (Umeda et al, 2015), leading to a patient-specific iPSC-based disease modeling study (Yokoyama, et al., 2015).
   1. Wang Y, Nakayama N. WNT and BMP signaling are both required for hematopoietic cell development from human ES cells. Stem Cell Res. 2009;3(2-3):113-125. PMI: 19595658
   2. Wang Y, Umeda K, Nakayama N. Collaboration between WNT and BMP signaling promotes hemoangiogenic cell development from human fibroblast-derived iPS cells. Stem Cell Res. 2010;4(3):223-231. PMI: 20493456
   3. Umeda K, Zhao J, Simmons P, Stanley E, Elefanty A, Nakayama N. Human chondrogenic paraxial mesoderm, directed specification and prospective isolation from pluripotent stem cells. Sci. Rep. 2012;2:455. PMI: 22701159
   4. Mae S, Shono A, Shiota F, Yasuno T, Kajiwara M, Gotoda-Nishimura N, et al. Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nat Commun. 2013;4:1367. PMI: 23340407. Nakayama N, coauthor
   5. Yokoyama K, Ikeya M, Umeda K, Oda, H, Nodomi, S, Nasu, A, et al. Enhanced Chondrogenesis of Induced Pluripotent Stem Cells From Patients With Neonatal-Onset Multisystem Inflammatory Disease Occurs via the Caspase 1-Independent cAMP/Protein Kinase A/CREB Pathway. Arthritis Rheumatol. 2015;67(1):302-314. PMI: 25302486 Nakayama N, coauthor
   6. Umeda K, Oda H, Yan Q, Matthias N, Zhao J, Davis BR, et al. Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells. Stem Cell Reports. 2015;4(4):712-726. PMI: 25818812 Nakayama N, corresponding author
3. Controlling chondrocyte hypertrophic differentiation in tissue-engineered cartilage. This program aims to solve the second of the two major problems that adult MSC-based cartilage regeneration faces: i.e., suppressing (endochondral) ossification of the regenerated chondrocytes. Chondrocytes derived from the hPSC-derived SOX9+ chondroprogenitors and adult MSCs are readily committed to endochondral ossification in vitro and in vivo. Forskolin, adenylyl cyclase activator, significantly suppress such tendency (Lee, et al., 2018). However, the suppression is not complete. Recently Naoki’s group has found ways to give rise to GDF5+ joint progenitor-like cells that develop articular-like stable cartilage without showing signs of endochondral ossification in vitro and in vivo (Pothiawala, et al., 2021). Naoki’s group has been interacting with Dr. Johnny Huard’s group to elucidate ways to educate adult stem cells to behave similarly to the GDF5+ joint progenitor-like cells to preferentially regenerate articular-like stable cartilage, via basic studies of the hPSC-derived GDF5+ cells.
   1. Li H, Lu A, Tang Y, Beckman S, Nakayama N, Poddar M, et al. The superior regenerative potential of muscle-derived stem cells for articular cartilage repair is attributed to high cell survival and chondrogenic potential. Mol Ther Methods Clin Dev. 2016;3:16065. PMI: 27990446
   2. Lee, JY, Matthias, N, Pothiawala, A, Ang, BK, Lee, M, Li, J, et al. Pre-transplantational control of the post-transplantational fate of human pluripotent stem cell-derived cartilage. Stem Cell Reports. 2018;11(2):440-453. PMI: 30057264. Nakayama N, corresponding author
   3. Pothiawala A, Sahbazoglu BE, Ang BK, Matthias N, Pei G, Yan Q, Davis BR, Huard J, Zhao Z, Nakayama N. GDF5+ chondroprogenitors derived from human pluripotent stem cells preferentially form permanent chondrocytes. Development. 2021.

Research Support

Ongoing Funding:

1. 1R01AR077045-01A1, NIAMS NIH (Nakayama, N., PI) 04/01/2021-03/31/2026
   “Articular Cartilage Tissue Engineering with Human Pluripotent Stem Cells”
   Our overarching hypothesis is that the novel human pluripotent stem cell derived GDF5+ mesenchymal cells represent the human embryonic joint progenitor cells and provide a better cell source for articular cartilage repair.

Pending Support:

1. 1R21AR079075-01A1, NIAMS NIH (Nakayama, N., mPI, Huard, J., cPI, Guilak, F., mPI) Priority score 6.0%.
   “SMART Stem Cells that Autonomously Down-modulate TGF- signaling for Articular Cartilage Repair”
   This project aims to test the novel technical concept of autonomous inhibition of extracellular (i.e., TGF-) signaling for cartilage repair.

Past Grant Supports: 

1. Annie and Bob Graham Distinguished Chair in Stem Cell Biology, UTHealth Medical School (Nakayama, N., PI) 11/01/14-08/31/19
   Endowment
2. Just-missed-grant Fund, UTHealth Medical School (Nakayama, N., PI) 06/01/14-05/31/15
   “Toward permanent cartilage-formation, GDF5+ joint progenitor like cells from hPSCs “
3. Jerold B. Katz Distinguished Professorship in Stem Cell Research, UTHealth Medical School (Nakayama, N., PI) 02/01/14-10/30/14
   Endowment
4. Innovative Research Grant, Arthritis Foundation (Nakayama, N., PI) 03/01/12-02/28/14
   “Making the hES/iPS cell-derived chondroprogenitor a novel therapeutic tool”
   This study seeks to establish methods to generate lineage-specific chondroprogenitor cells from human pluripotent stem cells.
5. The Rolanette and Berdon Lawrence Research Award, The Rolanette and Berdon Lawrence Bone Disease Program of Texas (Nakayama, N., PI) 9/01/11-8/31/13
   “Human pluripotent stem cell as an alternative cell source for bone and cartilage regenerative therapy”
6. 1RC1HL099335-01, NHBLI, NIH (Nakayama, N., PI) 04/01/10-03/31/13
   “There will be Blood: Stem cell niche driven derivation of HSC from ES cells”
   This study seeks to establish methods to generate hematopoietic stem cells from human embryonic stem cells.
7. Start-up Funding, Brown Foundation (Nakayama, N., PI) 08/01/08-10/31/13
   Research funding to support the pioneering work on the chondrogenesis from human pluripotent stem cells
8. P045 Stem Cell Research Grant, States of Victoria and New South Wales, Australia (Nakayama, N., PI; Laslett, A., Victorian PD) 07/01/08-06/30/09
   “Production of patient specific pluripotent stem cell lines and their characterization”
   This study seeks to establish patient specific pluripotent stem cells (NSW) and characterizing their growth and differentiation properties (VIC).
9. P009 Haemopoiesis-Stem Cell Differentiation, Australian Stem Cell Centre (Nakayama, N., PI) 07/01/06-06/30/09
   This study seeks to establish mesenchymal stem cells, haematopoietic stem cells and cardiomyogenic progenitor cells from mouse and human embryonic stem cells.
10. P017 Haemopoiesis (Nakayama, N., CI; Simmons, P., PI) Australian Stem Cell Centre’s Haemopoiesis Therapeutic Focus (Elefanty, A., PD) 04/01/04-06/30/06
    This study seeks to generate haematopoietic stem cells from mouse embryonic stem cells.
11. P015 Stem Cell Differentiation (Nakayama, N., PI) Australian Stem Cell Centre’s Adult Stem Cell Platform (Simmons, P., PD) 04/01/04-06/30/06
    This study seeks to establish a research platform for studying proliferation and differentiation of adult as well as embryonic stem cells, using genomics technologies.