In vivo functional and transcriptional profiling of bone marrow stem cells after transplantation into ischemic myocardium.
OBJECTIVE
Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model.


RESULTS
We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis.


CONCLUSIONS
Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Ahmad Y
AY
Sheikh
Bruno C
BC
Huber
Kazim H
KH
Narsinh
Joshua M
JM
Spin
Koen
K
van der Bogt
Patricia E
PE
de Almeida
Katherine J
KJ
Ransohoff
Daniel L
DL
Kraft
Giovanni
G
Fajardo
Diego
D
Ardigo
Julia
J
Ransohoff
Daniel
D
Bernstein
Michael P
MP
Fischbein
Robert C
RC
Robbins
Joseph C
JC
Wu
D000818:Animals; D002470:Cell Survival; D004452:Echocardiography; D005260:Female; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D049268:Positron-Emission Tomography; D013997:Time Factors