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  1. Science & Research (Biologics)

Predicting the Safety and Efficacy of Cell and Tissue Products Used for Repair of Damaged Tissue and Structures through Cell Growth and Maturation Pathways

Principal Investigator: Malcolm Moos, MD, PhD
Office / Division / Lab: OTAT / DCGT / CTTB


General Overview

Tissues and organs can be damaged by accident, battle trauma, or disease. Improved methods of repair, replacement, or regeneration of damaged tissues and organs are an important public health goal. Novel biological products containing living cells show great promise for use as therapies in these settings, but design, manufacture, and testing of these products has proven very challenging.

A major obstacle to successful development of cellular therapies has been great uncertainty about how to test these products to be sure they are safe and effective. Most of this testing will need to focus on the basic mechanisms cells use to control their behavior, especially the differentiation of immature cells (such as stem cells) to mature forms. We can do experiments with frog embryos that are not possible with mammals that teach us a great deal about these mechanisms. Using this approach, we have found several proteins that act as signals controlling certain aspects of cell differentiation.

We have used a variety of methods to identify these signals, including identification and detailed examination of biological activities and chemical analysis of the purified molecules that control those activities, DNA amplification by polymerase chain reaction (PCR, a technique for making millions of copies of single pieces of DNA for study), and computer-based mathematical analysis of these pathways and how they control tissue and organ development. We then test the effects of individual molecules that are over-expressed (too much of the molecule), expressed in the wrong place, or under-expressed. This provides us with a great deal of information about what a signaling molecule can do, and what processes it is essential for. We can then do additional experiments to see what known signal pathways the molecule interacts with.

This approach has identified molecules that are now being evaluated as therapeutic products and biomarkers (molecules whose presence reflects specific states of activity, disease, response to drugs, potency, and other characteristics of cells and tissues). Biomarkers will be very valuable tools for manufacturing engineered tissues and for testing products.


Scientific Overview

Our objective is to identify signals and signal pathways critical for controlling cell fate decisions in order to develop improved methods for evaluating experimental cell-based products analytically both for process controls and release specifications that predict product performance reliably. The research program exploits a vertebrate embryology model that is particularly useful for identifying the key biological mechanisms controlling repair and regeneration and the interactions between them We focus on the medically critical but complicated process of joint development and perform detailed functional analyses of the proteins involved. We have identified several molecules that help control processes such as joint morphogenesis, blood development, and formation of the nervous system.

This work has also uncovered ways in which different proteins cooperate to achieve precisely localized control of tissue and organ development during the formation of complex structures such as the vertebrate joint, eye, or even overall body plan. We have identified both novel proteins (ADMP, CDMP1, CDMP2, FRZB) and novel functions for known proteins (SMOC, SPC7). We have used classical protein purification and protein microsequencing, degenerate PCR, and computational screens to identify molecules of interest. We then study their function and biological distribution in the experimentally tractable Xenopus embryo, relying heavily on gain-of-function and loss-of- function studies in which mRNA or antisense morpholino oligonucleotides, respectively, are microinjected in targeted regions of the embryo.

Finally, our approach has not only identified the novel molecules and functions mentioned previously, but also provided new insights into control of both the Bone Morphogenetic Protein and Wnt signaling pathways. Several of the molecules are being evaluated as therapeutic products, biomarkers for testing of cellular products, or reagents for use in tissue engineering.


Publications

  1. Curr Microbiol 2023 Jun 24;80(8):253
    Neisseria montereyensis sp. nov., isolated from oropharynx of California sea lion (Zalophus californianus): genomic, phylogenetic, and phenotypic study.
    Volokhov DV, Zagorodnyaya TA, Furtak VA, Nattanmai G, Randall L, Jose S, Gao Y, Gulland FM, Eisenberg T, Delmonte P, Blom J, Mitchell KK
  2. J Extracell Vesicles 2023 Feb;12(2):e12305
    Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases.
    Li G, Chen T, Dahlman J, Eniola-Adefeso L, Ghiran IC, Kurre P, Lam WA, Lang JK, Marbán E, Martín P, Momma S, Moos M, Nelson DJ, Raffai RL, Ren X, Sluijter JPG, Stott SL, Vunjak-Novakovic G, Walker ND, Wang Z, Witwer KW, Yang PC, Lundberg MS, Ochocinska MJ, Wong R, Zhou G, Chan SY, Das S, Sundd P
  3. iScience 2022 Aug 19;25(8):104686
    Single-nucleus chromatin accessibility and RNA sequencing reveal impaired brain development in prenatally e-cigarette exposed neonatal rats.
    Chen Z, Chen W, Li Y, Moos M Jr, Xiao D, Wang C
  4. Mol Cell Probes 2022 Aug;64:101833.
    Robust humoral immune response against rabies virus in rabbits and Guinea pigs immunized with plasmid DNA vectors encoding rabies virus glycoproteins--an approach to the production of polyclonal antibody reagents.
    Volokhov DV, Furtak V, Allen C, Pulle G, Zajac MD, Levin Y, Kochba E, Moore SM
  5. Mol Cell Probes 2022 Jun;63:101815
    An ELISA-based antigenicity test of rabies recombinant glycoprotein cannot predict its protective potency in vivo.
    Volokhov DV, Fry AM, Furtak V, Jones RM, Musiychuk K, Norikane J, Green BJ, Srinivas GB, Streatfield SJ, Yusibov V
  6. Genome Biol 2022 Jan 7;23(1):12
    Achieving robust somatic mutation detection with deep learning models derived from reference data sets of a cancer sample.
    Sahraeian SME, Fang LT, Karagiannis K, Moos M, Smith S, Santana-Quintero L, Xiao C, Colgan M, Hong H, Mohiyuddin M, Xiao W
  7. Nat Biotechnol 2021 Sep;39(9):1141-50
    Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing.
    Xiao W, Ren L, Chen Z, Fang LT, Zhao Y, Lack J, Guan M, Zhu B, Jaeger E, Kerrigan L, Blomquist TM, Hung T, Sultan M, Idler K, Lu C, Scherer A, Kusko R, Moos M, Xiao C, Sherry ST, Abaan OD, Chen W, Chen X, Nordlund J, Liljedahl U, Maestro R, Polano M, Drabek J, Vojta P, Kõks S, Reimann E, Madala BS, Mercer T, Miller C, Jacob H, Truong T, Moshrefi A, Natarajan A, Granat A, Schroth GP, Kalamegham R, Peters E, Petitjean V, Walton A, Shen TW, Talsania K, Vera CJ, Langenbach K, de Mars M, Hipp JA, Willey JC, Wang J, Shetty J, Kriga Y, Raziuddin A, Tran B, Zheng Y, Yu Y, Cam M, Jailwala P, Nguyen C, Meerzaman D, Chen Q, Yan C, Ernest B, Mehra U, Jensen RV, Jones W, Li JL, Papas BN, Pirooznia M, Chen YC, Seifuddin F, Li Z, Liu X, Resch W, Wang J, Wu L, Yavas G, Miles C, Ning B, Tong W, Mason CE, Donaldson E, Lababidi S, Staudt LM, Tezak Z, Hong H, Wang C, Shi L
  8. Nat Biotechnol 2021 Sep;39(9):1151-60
    Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing.
    Fang LT, Zhu B, Zhao Y, Chen W, Yang Z, Kerrigan L, Langenbach K, de Mars M, Lu C, Idler K, Jacob H, Zheng Y, Ren L, Yu Y, Jaeger E, Schroth GP, Abaan OD, Talsania K, Lack J, Shen TW, Chen Z, Stanbouly S, Tran B, Shetty J, Kriga Y, Meerzaman D, Nguyen C, Petitjean V, Sultan M, Cam M, Mehta M, Hung T, Peters E, Kalamegham R, Sahraeian SME, Mohiyuddin M, Guo Y, Yao L, Song L, Lam HYK, Drabek J, Vojta P, Maestro R, Gasparotto D, Kõks S, Reimann E, Scherer A, Nordlund J, Liljedahl U, Jensen RV, Pirooznia M, Li Z, Xiao C, Sherry ST, Kusko R, Moos M, Donaldson E, Tezak Z, Ning B, Tong W, Li J, Duerken-Hughes P, Catalanotti C, Maheshwari S, Shuga J, Liang WS, Keats J, Adkins J, Tassone E, Zismann V, McDaniel T, Trent J, Foox J, Butler D, Mason CE, Hong H, Shi L, Wang C, Xiao W, Somatic Mutation Working Group of Sequencing Quality Control Phase II Consortium
  9. Nat Biotechnol 2021 Sep;39(9):1103-14
    A multicenter study benchmarking single-cell RNA sequencing technologies using reference samples.
    Chen W, Zhao Y, Chen X, Yang Z, Xu X, Bi Y, Chen V, Li J, Choi H, Ernest B, Tran B, Mehta M, Kumar P, Farmer A, Mir A, Mehra UA, Li JL, Moos M Jr, Xiao W, Wang C
  10. Sci Data 2021 Feb 2;8(1):39
    A multi-center cross-platform single-cell RNA sequencing reference dataset.
    Chen X, Yang Z, Chen W, Zhao Y, Farmer A, Tran B, Furtak V, Moos M Jr, Xiao W, Wang C
  11. J Tissue Eng Regen Med 2018 Mar;12(3):794-807
    Limb derived cells as a paradigm for engineering self-assembling skeletal tissues.
    Fernando WA, Papantoniou I, Mendes LF, Hall GN, Bosmans K, Tam WL, Teixeira LM, Moos M Jr, Geris L, Luyten FP
  12. Cytotherapy 2018 Mar;20(3):343-60
    Variation in primary and culture-expanded cells derived from connective tissue progenitors in human bone marrow space, bone trabecular surface and adipose tissue.
    Qadan MA, Piuzzi NS, Boehm C, Bova W, Moos M Jr., Midura RJ, Hascall VC, Malcuit C, Muschler GF
  13. Elife 2017 Mar 21;6:e17935
    SMOC can act as both an antagonist and an expander of BMP signaling.
    Thomas JT, Eric Dollins D, Andrykovich KR, Chu T, Stultz BG, Hursh DA, Moos M
  14. PLoS One 2016 Apr 21;11(4):e0154294
    SMOC binds to pro-EGF, but does not induce Erk phosphorylation via the EGFR.
    Thomas JT, Chhuy-Hy L, Andrykovich KR, Moos M Jr

 

 
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