Vaccines, Blood & Biologics

Ensuring Safety and Efficacy of Stem Cell-based Products

Principal Investigator: Steven R. Bauer, PhD
Office / Division / Lab: OCTGT / DCGT / CTTB

General Overview

Cell-based therapies show great promise for repairing, replacing, restoring, or regenerating damaged cells, tissues and organs. Researchers are working to develop cell-based treatments that are both effective and safe.

Many cell-based therapies use stem cells (SC) that are removed from the body and put into cultures in the laboratory, where they multiply before being infused into the patient. SCs are immature cells that replicate themselves and have the ability to give rise to a variety of different types of cells.

For cell therapies based on embryonic stem cells, stem cells are first stimulated to mature before they are given to a patient. However, embryonic stem cells can cause tumors so products based on them carefully avoid having any remaining embryonic stem cells in the product given to patients. Also, these more mature cells may be better suited to replace specific types of damaged or lost cells or for repairing damaged tissue.

A major challenge posed by SC therapy is the need to ensure their efficacy and safety. Cells manufactured in large quantities outside their natural environment in the human body can become ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune reactions, or growth of unwanted tissue. In response to this challenge, FDA scientists are developing laboratory techniques that will enable the agency to carefully evaluate and characterize these products in order to reliably predict whether they will be safe and effective. Our laboratories use cell cultures and animal models to develop such techniques and to study the biochemical signals that govern cell behavior during manufacturing and after administration to patients. These studies will help us develop testing methods that are practical and applicable to specific manufacturing steps. This will help CBER to ensure the consistency, safety, and efficacy of stem cell-based products.

Scientific Overview

Our research program uses animal models and cell cultures to study how cells multiply and differentiate (mature into specialized cells with limited, specific functions). We also study the effects on cells of their microenvironment, both inside and outside of the body. The microenvironment is the immediate area around cells. Parts of the microenvironment include other cell types, and other tissues and growth factors that have a localized effect on how the cells grow, divide, or migrate. Part of the microenvironment is the extracellular matrix made up of a carbohydrate-protein gel. The extracellular matrix helps to support the cell and cushion it from physical stress; it also serves as a means through which cells communicate with each other by releasing signaling molecules.

The communication among cells, as well as the time and conditions in which cells grow exert significant influence on stem or progenitor cell proliferation and differentiation. Progenitor cells are stem cells that have differentiated enough to be committed to becoming a certain general type of cell, and will eventually differentiate into a specific cell.

Our objective is to identify the molecules that exert critical influence on the growth and differentiation of SCs. Such molecules can be used in tests that evaluate and characterize cells during the manufacturing process and as lot-release measurements for cell-therapy products. Lot release tests are done before products are shipped out of manufacturing facilities in order to ensure their safety and quality.

We have developed tests that help us to determine how likely specific populations of progenitor cells called mesenchymal stem cells (MSCs) will successfully give rise to fat and bone.

One of our major efforts is the hunt for molecular biomarkers--molecules whose presence reflects specific states of activity, disease, response to drugs, potency, and other characteristics of cells and tissues. In order to discover biomarkers on MSCs we use a variety of technologies. Our major tools are microarrays (devices that enable the study of the state of activity of tens of thousands of genes at a time), RT-PCR (a technique for rapidly making thousands of copies of pieces of DNA), and flow cytometry (a technique for automatically identifying, counting and examining very large numbers of cells).

We are now studying the role of a protein called DLK in a strain of mouse that is genetically deficient in this protein. In these mice we found that DLK influences the generation of MSCs and their ability to turn into fat. Our studies have also shown that DLK influences development of B-lymphocytes, the immune system cells that produce antibodies.

We are also using MSCs from this mouse strain to study exactly how DLK helps to control the development of fat tissue and discovered previously unknown roles that DLK plays in this process. We've gained important new insights into interactions between MSC cells and between MSC cells and the cells that give rise to B lymphocytes. These studies will likely help us to develop improved methods for testing MSC products to ensure they will be safe and effective when used as therapies. This new knowledge will also help us to discover biomarkers for testing MSC-based products.


Curr Protoc Cytom 2016 Jan 6;75:1.29.1-1.29.14
Quantitative flow cytometry measurements in antibodies bound per cell based on a CD4 reference.
Wang L, Degheidy H, Abbasi F, Mostowski H, Marti G, Bauer S, Hoffman RA, Gaigalas AK

Data Brief 2015 Nov 1;5:864-70
The proteomic dataset for bone marrow derived human mesenchymal stromal cells: effect of in vitro passaging.
Mindaye ST, Lo Surdo J, Bauer SR, Alterman MA

Stem Cell Res 2015 Oct 30;15(3):655-64
System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation.
Mindaye ST, Surdo JL, Bauer SR, Alterman MA

Stem Cells 2015 Jul;33(7):2169-81
Chromatin changes at the PPAR-γ2 promoter during bone marrow-derived multipotent stromal cell culture correlate with loss of gene activation potential.
Lynch PJ, Thompson EE, McGinnis K, Rovira Gonzalez YI, Lo Surdo J, Bauer SR, Hursh DA

BMC Biology 2014 Dec 31;12:771
Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.
Madon-Simon M, Cowley M, Garfield AS, Moorwood K, Bauer SR, Ward A

Thromb Haemost 2014 Sep 29;112(4):770-80
Isolation of a circulating CD45-, CD34dim cell population and validation of their endothelial phenotype.
Tropea MM, Harper BJ, Graninger GM, Phillips TM, Ferreyra G, Mostowski HS, Danner RL, Suffredini AF, Solomon MA

Stem Cell Res Ther 2014 Apr 28;5(2):59
Gene markers of cellular aging in human multipotent stromal cells in culture.
Bellayr IH, Catalano JG, Lababidi S, Yang AX, Lo Surdo JL, Bauer SR, Puri RK

Science 2014 Mar 14;343(6176):1264-6
Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution.
Muller D1, Cherukuri P, Henningfeld K, Poh CH, Wittler L, Grote P, Schlüter O, Schmidt J, Laborda J, Bauer SR, Brownstone RM, Marquardt T

Cell Stem Cell 2014 Feb 6;14(2):141-5
MSC-based product characterization for clinical trials: an FDA perspective.
Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR

J Biol Chem 2014 Feb 7;289(6):3811-24
A missense mutation in Rev7 disrupts formation of Polζ, impairing mouse development and repair of genotoxic agent-induced DNA lesions.
Khalaj M, Abbasi A, Yamanishi H, Akiyama K, Wakitani S, Kikuchi S, Hirose M, Yuzuriha M, Magari M, Degheidy HA, Abe K, Ogura A, Hashimoto H, Kunieda T

Cytotherapy 2013 Dec;15(12):1527-40
Automated microscopy as a quantitative method to measure differences in adipogenic differentiation in preparations of human mesenchymal stromal cells.
Lo Surdo JL, Millis BA, Bauer SR

Stem Cell Res Ther 2013;4(5):128
Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro.
Nazarov C, Lo Surdo J, Bauer SR, Wei CH

Cytometry B Clin Cytom 2013 Jul;84(4):237-47
Bcl-2 level as a biomarker for 13q14 deletion in CLL.
Degheidy HA, Gadalla SM, Farooqui MZ, Abbasi F, Arthur DC, Bauer SR, Wilson WH, Wiestner A, Stetler-Stevenson MA, Marti GE

Nanomedicine 2013 Jul;9(5):594-9
Continuing to strengthen FDA's science approach to emerging technologies.
Anatol R, Bauer S, Epstein S, Filice R, Lauritsen K, Lee MH, Mansfield E, McMurry-Heath M, Milone J, Pena C, Pollack S, Zineh I

Stem Cell Res 2013 Jun 2;11(2):793-805
Global proteomic signature of undifferentiated human bone marrow stromal cells: evidence for donor-to-donor proteome heterogeneity.
Mindaye ST, Ra M, Lo Surdo JL, Bauer SR, Alterman MA

Haematologica 2013 Feb;98(2):163-171
Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells.
Mirshekar-Syahkal B, Haak E, Kimber GM, van Leusden K, Harvey K, O' Rourke J, Laborda J, Bauer SR, de Bruijn MF, Ferguson-Smith AC, Dzierzak E, Ottersbach K

J Proteomics 2013 Jan 14;78:1-14
Improved proteomic profiling of the cell surface of culture-expanded human bone marrow multipotent stromal cells.
Mindaye ST, Ra M, Losurdo J, Bauer SR, Alterman MA

Blood 2012 Nov 16;120(21):1251
B Cell Development and the Splenic Microenvironment in Dlk-1 Deficient Mice
Degheidy HA, Branchaw AL, Bauer LC, Bauer SR

Tissue Eng Part C Methods 2012 Nov;18(11):877-89
Quantitative approaches to detect donor and passage differences in adipogenic potential and clonogenicity in human bone marrow-derived multipotent stromal cells.
Lo Surdo JL, Bauer SR

Nature 2011 Jul 20;475(7356):381-5
Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis.
Ferron SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, Morante-Redolat JM, Laborda J, Guillemot F, Bauer SR, Farinas I, Ferguson-Smith AC

J Autoimmun 2009 Feb;32(1):14-23
Regulatory T cells as central regulators of both autoimmunity and B cell malignancy in New Zealand Black mice.
Scaglione BJ, Salerno E, Gala K, Pan M, Langer JA, Mostowski HS, Bauer S, Marti G, Li Y, Tsiagbe VK, Raveche ES

Stem Cells Dev 2008 Jun;17(3):495-507
Dlk1 Influences Differentiation and Function of B Lymphocytes.
Raghunandan R, Ruiz-Hidalgo M, Jia Y, Ettinger R, Rudikoff E, Riggins P, Farnsworth R, Tesfaye A, Laborda J, Bauer SR

Medicine 2008 Mar;87(2):70-86
Predictors of Acquired Lipodystrophy in Juvenile-Onset Dermatomyositis and a Gradient of Severity.
Bingham A, Mamyrova G, Rother KI, Oral E, Cochran E, Premkumar A, Kleiner D, James-Newton L, Targoff IN, Pandey JP, Carrick DM, Sebring N, O'Hanlon TP, Ruiz-Hidalgo M, Turner M, Gordon LB, Laborda J, Bauer SR, Blackshear PJ, Imundo L, Miller FW, Rider LG, Childhood Myositis Heterogeneity Study Group

Br J Haematol 2007 Dec;139(5):630-4
Chronic lymphocytic leukaemia genetics overview.
Caporaso N, Goldin L, Plass C, Calin G, Marti G, Bauer S, Raveche E, McMaster ML, Ng D, Landgren O, Slager S

J Virol 2007 Jan;81(1):261-71
Identification of linear heparin binding peptides derived from the human respiratory syncytial virus fusion glycoprotein that inhibit infectivity.
Crim RL, Audet SA, Feldman SA, Mostowski HS, Beeler JA

Stem Cells 2006 Dec;24(12):2611-7
Transforming growth factor-beta1 sensitivity is altered in Abl-Myc- and Raf-Myc-induced mouse pre-B-cell tumors.
Letterio J, Rudikoff E, Voong N, Bauer SR

BMC Genomics 2005 Nov 2;6:150
Proposed methods for testing and selecting the ERCC external RNA controls.
External RNA Controls Consortium

Nat Methods 2005 Oct;2(10):731-4
The External RNA Controls Consortium: a progress report.
Baker SC, Bauer SR, Beyer RP, Brenton JD, Bromley B, Burrill J, Causton H, Conley MP, Elespuru R, Fero M, Foy C, Fuscoe J, Gao X, Gerhold DL, Gilles P, Goodsaid F, Guo X, Hackett J, Hockett RD, Ikonomi P, Irizarry RA, Kawasaki ES, Kaysser-Kranich T, Kerr K, Kiser G, Koch WH, Lee KY, Liu C, Liu ZL, Lucas A, Manohar CF, Miyada G, Modrusan Z, Parkes H, Puri RK, Reid L, Ryder TB, Salit M, Samaha RR, Scherf U, Sendera TJ, Setterquist RA, Shi L, Shippy R, Soriano JV, Wagar EA, Warrington JA, Williams M, Wilmer F, Wilson M, Wolber PK, Wu X, Zadro R; External RNA Controls Consortium


Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

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Building 71 Room 3103

Silver Spring, MD 20993-0002

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