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Bone Marrow-Derived B Cells Preserve Ventricular Function After Acute Myocardial Infarction

Traci T. Goodchild, PhD^_*,, Keith A. Robinson, PhD, Wenxin Pang, MD^_*,, Fernando Tondato, MD, PhD, Jianhua Cui, MD, Johnail Arrington, MS^_*, Lisa Godwin, AS, Mark Ungs, BS, MBA^_*, Nadia Carlesso, MD, PhD, Nadine Weich, PhD^_*, Mark C. Poznansky, MD, PhD, Nicolas A.F. Chronos, MD^_*,,_*

^_* AC Therapeutics, Inc., Norcross, Georgia
Saint Joseph's Translational Research Institute (formerly American Cardiovascular Research Institute), Atlanta, Georgia
Indiana School of Medicine, Indianapolis, Indiana
Infectious Diseases Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

^_* Reprint requests and correspondence: Dr. Nicolas A. F. Chronos, Saint Joseph's Research Institute, 5673 Peachtree-Dunwoody Road, Atlanta, Georgia 30342 (Email: nchronos{at}sjha.org).

Objectives: In view of evidence that mature cells play a role in modulating the stem cell niche and thereby stem cell potential and proliferation, we hypothesized that a mature bone marrow (BM) mononuclear cell (MNC) infusion subfraction may have particular potency in promoting hematopoietic or resident stem cell-induced cardiac repair post-infarction.

Background: Treatment of acute myocardial infarction (MI) with BM MNC infusion has shown promise for improving patient outcomes. However, clinical data are conflicting, and demonstrate modest improvements. BM MNCs consist of different subpopulations including stem cells, progenitors, and differentiated leukocytes.

Methods: Stem cells (c-kit+) and subsets of mature cells including myeloid lineage, B and T-cells were isolated from bone marrow harvested from isogeneic donor rats. Recipient rats had baseline echocardiography then coronary artery ligation; 1 x 10⁶ cells (enriched subpopulations or combinations of subpopulations of BM MNC) or saline was injected into ischemic and ischemic border zones. Cell subpopulations were either injected fresh or after overnight culture. After 2 weeks, animals underwent follow-up echocardiography. Cardiac tissue was assayed for cardiomyocyte proliferation and apoptosis.

Results: Fractional ventricular diameter shortening was significantly improved compared with saline (38 ± 3.2%) when B cells alone were injected fresh (44 ± 3.0%, p = 0.035), or after overnight culture (51 ± 2.9%, p < 0.001), or after culture with c-kit+ cells (44 ± 2.4%, p = 0.062). B cells reduced apoptosis at 48 h after injection compared with control cells (5.7 ± 1.2% vs. 12.6 ± 2.0%, p = 0.005).

Conclusions: Intramyocardial injection of B cells into early post-ischemic myocardium preserved cardiac function by cardiomyocyte salvage. Other BM MNC subtypes were either ineffective or suppressed cardioprotection conferred by an enriched B cell population.

Key Words: stem cells • myocardial infarction • cell therapy • regenerative medicine • myocardial repair

Abbreviations and Acronyms   BM = bone marrow   BrdU = 5-bromo-2'-deoxyuridine pellets   HSC = hematopoietic stem cell   LAD = left anterior descending artery   LV = left ventricle/ventricular   MI = myocardial infarction   MNC = mononuclear cell   NHSC = nonhematopoietic stem cell