The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts With Postinfarct LV Remodeling

Abstract

Cellular therapy for myocardial repair has been one of the most intensely investigated interventional strategies for acute myocardial infarction. Although the therapeutic potential of stem cells has been demonstrated in various studies, the underlying mechanisms for such improvements are poorly understood. In the present study, we investigated the long-term effects of stem cell therapy on both myocardial fiber organization and regional contractile function using a rat model of postinfarct remodeling. Human nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs) were administered via tail vein to rats 2 days after infarct surgery. Animals were maintained without immunosuppressive therapy. In vivo and ex vivo MR imaging was performed on infarct hearts 10 months after cell transplantation. Compared to the age-matched rats exposed to the identical surgery, both global and regional cardiac functions of the nh-UCBSC-treated hearts, such as ejection fraction, ventricular strain, and torsion, were significantly improved. More importantly, the treated hearts exhibited preserved fiber orientation and water diffusivities that were similar to those in sham-operated control hearts. These data provide the first evidence that nh-UCBSC treatment may prevent/delay untoward structural remodeling in postinfarct hearts, which supports the improved LV function observed in vivo in the absence of immunosuppression, suggesting a beneficial paracrine effect occurred with the cellular therapy.

Figure 1

Segmentation of LV into three segments. Segmentation of the LV into the infarct, border, and remote zones in a fixed (a) and in vivo (b) heart from the MI group, and a fixed (c) and in vivo (d) heart from the control group.

Figure 2

Characteristics of in vivo cardiac function. Radial (a) and circumferential (b) strains at apex and ventricular torsion (c) in CONT, MI, and MI+Cell groups. †Myocardial strains in the infarct zone of MI rats were not quantified due to significant wall thinning. ^*P<0.05 CONT versus MI. ^#P<0.05 MI versus MI+Cell.

Figure 3

Fiber helix angle distribution in fixed hearts. Histograms of fiber helix angles in the infarct (a), border (b), and remote (c) zones for CONT, MI and MI+Cell groups. ^*P<0.05 CONT versus MI. ^#P<0.05 MI versus MI+Cell.

Figure 4

Diffusivity and FA in fixed hearts. Mean water diffusivity (a) and fractional diffusion anisotropy (b) in the infarct, border, and remote zones for the CONT, MI and MI+Cell groups. ^*P<0.05 CONT versus MI. ^#P<0.05 MI versus MI+Cell.

Figure 5

Masson trichrome staining of fixed hearts. (a&c) Magnified pictures of scar zone of rat hearts from the MI group (b). (d&f) Magnified pictures of scar zone of rat hearts from the MI+Cell group (e). Color representation: nuclei, black; cytoplasm, red; muscle fiber, red; collagen, blue. (Bar = 1 mm) (g) Percentage of infarct area. (h) Percentage of wall thickness in infarct zone. (i) Percentage of fibrosis in infarct zone.

Figure 6

Quantification of c-kit⁺ cardiac progenitor cells. (a) Representative picture from a heart in the MI group. (b) Representative picture from a heart in the MI+cell group. (c) Quantification of c-kit⁺ cardiac progenitor cells. (Bar = 100μm; α-SA = α-sarcomere actin).

Figure 7

Dual fluorescent immunostaining for blood vessel (arterioles) density quantification. (a&b) Representative pictures of blood vessel density in infarct zone (a) and border zone (b) of the MI group. (c&d) Representative pictures of blood vessel density in infarct zone (c) and border zone (d) of the MI+cell group. Quantification of blood vessel density (number/400x magnification field) was based on immune-staining images for von Willebrand Factor-8 (vWF-8; e) and smooth muscle actin (SMA; f). Bar = 100 μm.